Alkanoic acid derivatives as αv integrin receptor antagonists

ABSTRACT

The present invention relates to compounds and derivatives thereof, their synthesis, and their use as integrin receptor antagonists. More particularly, the compounds of the present invention are antagonists of the integrin receptors αvβ3, αvβ5 and/or αvβ6 and are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, inflammatory arthritis, viral disease, and tumor growth and metastasis.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention is related to U.S. provisional application Ser.No. 60/096,378, filed Aug. 13, 1998, the contents of which are herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to compounds and derivatives thereof,their synthesis, and their use as integrin receptor antagonists. Moreparticularly, the compounds of the present invention are antagonists ofthe integrin receptors ανβ3, ανβ5 and/or ανβ6 and are useful forinhibiting bone resorption, treating and preventing osteoporosis, andinhibiting vascular restenosis, diabetic retinopathy, maculardegeneration, angiogenesis, atherosclerosis, inflammation, inflammatoryarthritis, viral disease, tumor growth, and metastasis.

BACKGROUND OF THE INVENTION

It is believed that a wide variety of disease states and conditions canbe mediated by acting on integrin receptors and that integrin receptorantagonists represent a useful class of drugs. Integrin receptors areheterodimeric transmembrane receptors through which cells attach andcommunicate with extracellular matrices and other cells. (See S. B.Rodan and G. A. Rodan, "Integrin Function In Osteoclasts," Journal ofEndocrinology, Vol. 154, S47-S56 (1997), which is incorporated byreference herein in its entirety).

In one aspect of the present invention, the compounds herein are usefulfor inhibiting bone resorption. Bone resorption is mediated by theaction of cells known as osteoclasts. Osteoclasts are largemultinucleated cells of up to about 400 mm in diameter that resorbmineralized tissue, chiefly calcium carbonate and calcium phosphate, invertebrates. Osteoclasts are actively motile cells that migrate alongthe surface of bone, and can bind to bone, secrete necessary acids andproteases, thereby causing the actual resorption of mineralized tissuefrom the bone. More specifically, osteoclasts are believed to exist inat least two physiological states, namely, the secretory state and themigratory or motile state. In the secretory state, osteoclasts are flat,attach to the bone matrix via a tight attachment zone (sealing zone),become highly polarized, form a ruffled border, and secrete lysosomalenzymes and protons to resorb bone. The adhesion of osteoclasts to bonesurfaces is an important initial step in bone resorption. In themigratory or motile state, the osteoclasts migrate across bone matrixand do not take part in resorption until they again attach to bone.

Integrins are involved in osteoclast attachment, activation andmigration. The most abundant integrin in osteoclasts, e.g., in rat,chicken, mouse and human osteoclasts, is an integrin receptor known asανβ3, which is thought to interact in bone with matrix proteins thatcontain the RGD sequence. Antibodies to ανβ3 block bone resorption invitro indicating that this integrin plays a key role in the resorptiveprocess. There is increasing evidence to suggest that ανβ3 ligands canbe used effectively to inhibit osteoclast mediated bone resorption invivo in mammals.

The current major bone diseases of public concern are osteoporosis,hypercalcemia of malignancy, osteopenia due to bone metastases,periodontal disease, hyperparathyroidism, periarticular erosions inrheumatoid arthritis, Paget's disease, immobilization-inducedosteopenia, and glucocorticoid-induced osteoporosis. All of theseconditions are characterized by bone loss, resulting from an imbalancebetween bone resorption, i.e. breakdown, and bone formation, whichcontinues throughout life at the rate of about 14% per year on theaverage. However, the rate of bone turnover differs from site to site;for example, it is higher in the trabecular bone of the vertebrae andthe alveolar bone in the jaws than in the cortices of the long bones.The potential for bone loss is directly related to turnover and canamount to over 5% per year in vertebrae immediately following menopause,a condition which leads to increased fracture risk.

In the United States, there are currently about 20 million people withdetectable fractures of the vertebrae due to osteoporosis. In addition,there are about 250,000 hip fractures per year attributed toosteoporosis. This clinical situation is associated with a 12% mortalityrate within the first two years, while 30% of the patients requirenursing home care after the fracture.

Individuals suffering from all the conditions listed above would benefitfrom treatment with agents which inhibit bone resorption.

Additionally, ανβ3 ligands have been found to be useful in treatingand/or inhibiting restenosis (i.e. recurrence of stenosis aftercorrective surgery on the heart valve), atherosclerosis, diabeticretinopathy, macular degeneration, and angiogenesis (i.e. formation ofnew blood vessels), and inhibiting viral disease. Moreover, it has beenpostulated that the growth of tumors depends on an adequate bloodsupply, which in turn is dependent on the growth of new vessels into thetumor; thus, inhibition of angiogenesis can cause tumor regression inanimal models (See Harrison's Principles of Internal Medicine, 12th ed.,1991, which is incorporated by reference herein in its entirety).Therefore, ανβ3 antagonists which inhibit angiogenesis can be useful inthe treatment of cancer by inhibiting tumor growth (See, e.g., Brooks etal., Cell, 79:1157-1164 (1994), which is incorporated by referenceherein in its entirety).

Evidence has also been presented suggesting that angiogenesis is acentral factor in the initiation and persistence of arthritic disease,and that the vascular integrin ανβ3 may be a preferred target ininflammatory arthritis. Therefore, ανβ3 antagonists which inhibitangiogenesis may represent a novel therapeutic approach to the treatmentof arthritic disease, such as rheumatoid arthritis (see C. M. Storgard,et al., "Decreased angiogenesis and arthritic disease in rabbits treatedwith an ανβ3 antagonist," J. Clin. Invest., 103: 47-54 (1999), which isincorporated by reference herein in its entirety).

Moreover, compounds of this invention can also inhibitneovascularization by acting as antagonists of the integrin receptor,ανβ5. A monoclonal antibody for ανβ5 has been shown to inhibitVEGF-induced angiogenesis in rabbit cornea and the chick chorioallantoicmembrane model (See M. C. Friedlander, et.al., Science 270:1500-1502(1995), which is incorporated by reference herein in its entirety).Thus, compounds that antagonize ανβ5 are useful for treating andpreventing macular degeneration, diabetic retinopathy, tumor growth, andmetastasis.

Additionally, compounds of the instant invention can inhibitangiogenesis and inflammation by acting as antagonists of the integrinreceptor, ανβ6, which is expressed during the later stages of woundhealing and remains expressed until the wound is closed (SeeChristofidou-Solomidou, et al., "Expression and Function of EndothelialCell a v Integrin Receptors in Wound-Induced Human Angiogenesis in HumanSkin/SCID Mice Chimeras, American Journal of Pathology, Vol. 151, No. 4,pp. 975-983 (October 1997), which is incorporated by reference herein inits entirety). It is postulated that ανβ6 plays a role in the remodelingof the vasculature during the later stages of angiogenesis. Also, ανβ6participates in the modulation of epithelial inflammation and is inducedin response to local injury or inflammation (See Xiao-Zhu Huang, et al.,"Inactivation of the Integrin β6 Subunit Gene Reveals a Role ofEpithelial Integrins in Regulating Inflammation in the Lungs and Skin,"Journal of Cell Biology, Vol. 133, No.4, pp. 921-928 (May 1996), whichis incorporated by reference herein in its entirety). Accordingly,compounds that antagonize ανβ6 are useful in treating or preventingcancer by inhibiting tumor growth and metastasis.

In addition, certain compounds of this invention antagonize both theανβ3 and ανβ5 receptors. These compounds, referred to as "dual ανβ3/ανβ5antagonists," are useful for inhibiting bone resorption, treating andpreventing osteoporosis, and inhibiting vascular restenosis, diabeticretinopathy, macular degeneration, angiogenesis, atherosclerosis,inflammation, inflammatory arthritis, viral disease, tumor growth, andmetastasis.

In addition, certain compounds of this invention are useful as mixedανβ3, ανβ5, and ανβ6 receptor antagonists.

Peptidyl as well as peptidomimetic antagonists of the ανβ3 integrinreceptor have been described both in the scientific and patentliterature. For example, reference is made to W.J. Hoekstra and B. L.Poulter, Curr. Med. Chem. 5: 195-204 (1998) and references citedtherein; WO 95/32710; WO 95/37655; WO 97/01540; WO 97/37655; WO98/08840; WO 98/18460; WO 98/18461; WO 98/25892; WO 98/31359; WO98/30542; WO 99/15506; WO 99/15507; EP 853084; EP 854140; EP 854145; andU.S. Pat. No. 5,780,426. Evidence of the ability of ανβ3 integrinreceptor antagonists to prevent bone resorption in vitro and in vivo hasbeen presented (see V. W. Engleman et al., "A Peptidomimetic Antagonistof the ανβ3 Integrin Inhibits Bone Resorption In Vitro and PreventsOsteoporosis In Vivo," J. Clin. Invest. 99: 2284-2292 (1997); S. B.Rodan et al., "A High Affinity Non-Peptide ανβ3 Ligand InhibitsOsteoclast Activity In Vitro and In Vivo," J. Bone Miner. Res. 11: S289(1996); J. F. Gourvest et al., "Prevention of OVX-Induced Bone Loss Witha Non-peptidic Ligand of the ανβ3 Vitronectin Receptor," Bone 23: S612(1998); M. W. Lark et al., "An Orally Active Vitronectin Receptor ανβ3Antagonist Prevents Bone Resorption In Vitro and In Vivo in theOvariectomized Rat," Bone 23: S219 (1998)).

The ανβ3 integrin receptor recognizes the Arg-Gly-Asp (RGD) tripeptidesequence in its cognate matrix and cell surface glycoproteins (see J.Samanen, et al., "Vascular Indications for Integrin ανAntagonists,"Curr. Pharmaceut. Design 3: 545-584(1997)). A benzazepine nucleus hasbeen employed among others by Genentech and SmithKline Beecham as aconformationally constrained Gly-Asp mimetic to elaborate nonpeptideανβ3 integrin receptor antagonists substituted at the N-terminus withheterocyclic arginine mimetics (see R. M. Keenan et al., "Discovery ofPotent Nonpeptide Vitronectin Receptor (ανβ3) Antagonists," J. Med.Chem. 40: 2289-2292 (1997); R. M. Keenan et al., "BenzimidazoleDerivatives As Arginine Mimetics in 1,4-Benzodiazepine NonpeptideVitronectin Receptor (ανβ3) Antagonists," Bioorg. Med. Chem. Lett. 8:3165-3170 (1998); and R. M. Keenan et al., "Discovery of anImidazopyridine-Containing 1,4-Benzodiazepine Nonpeptide VitronectinReceptor (ανβ3) Antagonist With Efficacy in a Restenosis Model," Bioorg.Med. Chem. Lett. 8: 3171-3176 (1998). Patents assigned to SmithKlineBeecham that disclose such benzazepine, as well as relatedbenzodiazepine and benzocycloheptene, ανβ3 integrin receptor antagonistsinclude WO 96/00574, WO 96/00730, WO 96/06087, WO 96/26190, WO 97/24119,WO 97/24122, WO 97/24124, WO 98/15278, WO 99/05107, WO 99/06049, WO99/15170, and WO 99/15178, and to Genentech include WO 97/34865. Thedibenzocycloheptene, as well as dibenzoxazepine, nucleus has also beenemployed as a Gly-Asp mimetic to afford ανβ3 antagonists (see WO97/01540, WO 98/30542, WO 99/11626, and WO 99/15508 all assigned toSmithKline Beecham).

However, there still remains a need for small-molecule, non-peptideselective integrin receptor antagonists that display improved potency,pharmacodynamic, and pharmacokinetic properties, such as oralbioavailability and duration of action, over already describedcompounds. Such compounds would prove to be useful for the treatment,prevention, or suppression of various pathologies enumerated above thatare mediated by integrin receptor binding and cell adhesion andactivation.

It is therefore an object of the present invention to provide compoundswhich are useful as integrin receptor antagonists.

It is another object of the present invention to provide compounds whichare useful as ανβ3 receptor antagonists.

It is another object of the present invention to provide compounds whichare useful as ανβ5 receptor antagonists.

It is another object of the present invention to provide compounds whichare useful as ανβ6 receptor antagonists.

It is another object of the present invention to provide compounds whichare useful as both ανβ3/ανβ5 receptor antagonists.

It is another object of the present invention to provide compounds whichare useful as mixed ανβ3, ανβ5 and ανβ6 receptor antagonists.

It is another object of the present invention to provide pharmaceuticalcompositions comprising integrin receptor antagonists.

It is another object of the present invention to provide methods formaking the pharmaceutical compositions of the present invention.

It is another object of the present invention to provide methods foreliciting an integrin receptor antagonizing effect in a mammal in needthereof by administering the compounds and pharmaceutical compositionsof the present invention.

It is another object of the present invention to provide compounds andpharmaceutical compositions useful for inhibiting bone resorption,restenosis, atherosclerosis, inflammation, inflammatory arthritis, viraldisease, diabetic retinopathy, macular degeneration, angiogenesis, tumorgrowth and metastasis.

It is another object of the present invention to provide compounds andpharmaceutical compositions useful for treating osteoporosis.

It is another object of the present invention to provide methods forinhibiting bone resorption, restenosis, atherosclerosis, inflammation,inflammatory arthritis, viral disease, diabetic retinopathy, maculardegeneration, angiogenesis, tumor growth and metastasis.

It is another object of the present invention to provide methods fortreating osteoporosis.

These and other objects will become readily apparent from the detaileddescription which follows.

SUMMARY OF THE INVENTION

The present invention relates to compounds having a structural formulaselected from the group consisting of ##STR1## wherein the dotted line arepresents a single or a double bond, provided that when a represents adouble bond, the double bond carbon atoms are substituted only with R¹⁰and R^(12;)

X is selected from the group consisting of ##STR2## a 5- or 6-memberedmonocyclic aromatic or nonaromatic ring system having 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O, and S whereinthe ring nitrogen atoms are unsubstituted or substituted with one R¹substituent and the ring carbon atoms are unsubstituted or substitutedwith one or two R¹ substituents, and

a 9- to 14-membered polycyclic ring system, wherein one or more of therings is aromatic, and wherein the polycyclic ring system has 1, 2, 3 or4 heteroatoms selected from the group consisting of N, O, and S whereinthe ring nitrogen atoms are unsubstituted or substituted with one R¹substituent and the ring carbon atoms are unsubstituted or substitutedwith one or two R¹ substituents;

Y is selected from the group consisting of

--(CH₂)_(m) --,

--(CH₂)_(m) --O--(CH₂)_(n) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --,

--(CH₂)_(m) --S--(CH₂)_(n) --,

--(CH₂)_(m) --SO--(CH₂)_(n) --,

--(CH₂)_(m) --SO₂ --(CH₂)_(n) --,

--(CH₂)_(m) --O--(CH₂)_(n) --O--(CH₂)_(p) --,

--(CH₂)_(m) --O--(CH₂)_(n) --NR⁴ --(CH₂)_(p) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --NR⁴ --(CH₂)_(p) --,

--(CH₂)_(m) --O--(CH₂)_(n) --S--(CH₂)_(p) --,

--(CH₂)_(m) --S--(CH₂)_(n) --S--(CH₂)_(p) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --S--(CH₂)_(p) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --O--(CH₂)_(p) --,

--(CH₂)_(m) --S--(CH₂)_(n) --O--(CH₂)_(p) --,

--(CH₂)_(m) --S--(CH₂)_(n) --NR⁴ --(CH₂)_(p) --, and

--(CH₂)_(m) --Z--(CH₂)_(n) --,

wherein Z is a 3- to 10-membered monocyclic or polycyclic aromatic ornonaromatic ring system having 0, 1, 2, 3, or 4 heteroatoms selectedfrom the group consisting of N, O, and S wherein the ring nitrogen atomsare unsubstituted or substituted with one R¹ substituent and the ringcarbon atoms are unsubstituted or substituted with one or two R¹substituents, and wherein any methylene (CH₂) carbon atom in Y, otherthan in R⁴, can be substituted by one or two R³ substituents; and

wherein R¹ and R² are each independently selected from the groupconsisting of

hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl,C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkyl C₁₋₆ alkyl, aryl, arylC₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₈alkyl, (C₁₋₆ alkyl)_(p) amino, (C₁₋₆ alkyl)_(p) amino C₁₋₈ alkyl, C₁₋₄alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl,hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, C₁₋₆alkyloxy-C₁₋₆ alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy,trifluoroethoxy, C₁₋₈ alkyl-S(O)_(p), (C₁₋₈ alkyl)_(p) aminocarbonyl,C₁₋₈ alkyloxycarbonylamino, (C₁₋₈ alkyl)_(p) aminocarbonyloxy, (arylC₁₋₈ alkyl)_(p) amino, (aryl)_(p) amino, aryl C₁₋₈ alkylsulfonylamino,and C₁₋₈ alkylsulfonylamino;

or two R¹ substituents, when on the same carbon atom, are taken togetherwith the carbon atom to which they are attached to form a carbonylgroup;

each R³ is independently selected from the group consisting of

hydrogen,

aryl,

C₁₋₁₀ alkyl,

aryl--(CH₂)_(r) --O--(CH₂)_(s) --,

aryl--(CH₂)_(r) S(O)_(p) --(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --,

halogen,

hydroxyl,

oxo,

trifluoromethyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

(C₁₋₆ alkyl)_(p) amino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl;

or two R³ substituents, when on the same carbon atom, are taken togetherwith the carbon atom to which they are attached to form a carbonyl groupor a cyclopropyl group,

wherein any of the alkyl groups of R³ are either unsubstituted orsubstituted with one to three R¹ substituents, and provided that each R³is selected such that in the resultant compound the carbon atom or atomsto which R³ is attached is itself attached to no more than oneheteroatom;

each R⁴ is independently selected from the group consisting of

hydrogen,

aryl,

aminocarbonyl,

C₃₋₈ cycloalkyl,

amino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl,

(aryl C₁₅ alkyl)_(p) aminocarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

C₁₋₈ alkyl,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,

C₁₋₈ alkylsulfonyl,

C₁₋₈ alkoxycarbonyl,

aryloxycarbonyl,

aryl C₁₋₈ alkoxycarbonyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

aryl C₁₋₆ alkylcarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

aminosulfonyl,

C₁₋₈ alkylaminosulfonyl,

(aryl)_(p) aminosulfonyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonyl,

arylsulfonyl,

aryl-C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylthiocarbonyl,

arylthiocarbonyl, and

aryl C₁₋₆ alkylthiocarbonyl,

wherein any of the alkyl groups of R⁴ are either unsubstituted orsubstituted with one to three R¹ substituents;

R⁵ and R⁶ are each independently selected from the group consisting of

hydrogen,

C₁₋₁₀ alkyl,

aryl,

aryl-(CH₂)_(r) --O--(CH₂)_(s) --,

aryl-(CH₂)_(r) S(O)_(p) --(CH₂)_(s) --,

aryl-(CH₂)_(r) --C(O)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --,

aryl--(CH₂)--N(R⁴)--C(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --,

halogen,

hydroxyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

(C₁₋₆ alkyl)_(p) amino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonyl amino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl;

or R⁵ and R⁶ are taken together with the carbon atom to which they areattached to form a carbonyl group,

wherein any of the alkyl groups of R⁵ or R⁶ are either unsubstituted orsubstituted with one to three R¹ substituents, and provided that each R⁵and R⁶ are selected such that in the resultant compound the carbon atomto which R⁵ and R⁶ are attached is itself attached to no more than oneheteroatom;

R⁷ and R⁸ are each independently selected from the group consisting of

hydrogen,

C₁₋₁₀ alkyl,

aryl,

aryl-(CH₂)_(r) --O--(CH₂)_(s) --,

aryl-(CH₂)_(r) S(O)_(p) --(CH₂)_(s) --,

aryl-(CH₂)_(r) --C(O)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --,

halogen,

hydroxyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

(C₁₋₆ alkyl)_(p) amino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylcarbonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

arylaminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl, (C₁₋ 8 alkyl)_(p)aminocarbonyl C₁₋ 6 alkyl,

(aryl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl, and

C₇₋₂₀ polycyclyl C₀₋₈ alkylsulfonylamino;

wherein any of the alkyl groups of R⁷ and R⁸ are either unsubstituted orsubstituted with one to three R¹ substituents,

and provided that each R⁷ and R⁸ are selected such that in the resultantcompound the carbon atom to which R⁷ and R⁸ are attached is itselfattached to no more than one heteroatom;

R⁹ is selected from the group consisting of

hydrogen,

C₁₋₈ alkyl,

aryl,

aryl C₁₋₈ alkyl,

C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

C₁₋₈ alkylaminocarbonylmethylene, and

C₁₋₈ dialkylaminocarbonylmethylene;

R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from the groupconsisting of

hydrogen,

C₁₋₈ alkyl,

aryl,

halogen,

hydroxyl,

aminocarbonyl,

C₃₋₈ cycloalkyl,

amino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl,

hydroxycarbonyl,

(aryl C₁₋₅ alkyl)_(p) aminocarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,

C₁₋₈ alkylsulfonyl,

C₁₋₈ alkoxycarbonyl,

aryloxycarbonyl,

aryl C₁₋₈ alkoxycarbonyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

aryl C₁₋₆ alkylcarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

aminosulfonyl,

C₁₋₈ alkylaminosulfonyl,

(aryl)_(p) aminosulfonyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonyl,

C₁₋₆ alkylsulfonyl,

arylsulfonyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylthiocarbonyl,

arylthiocarbonyl,

aryl C₁₋₆ alkylthiocarbonyl,

aryl-(CH₂)_(r) --O--(CH₂)_(s) --,

aryl-(CH₂)_(r) S(O)_(p) --(CH₂)_(s) --,

aryl-(CH₂)_(r) --C(O)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --,

aryl-(CH₂)_(r) N(R⁴)--(CH₂)_(s) --,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) amino,

aminocarbonyl C₁₋₆ alkyl,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl; or

R¹⁰ and R¹² are taken together with the carbon atoms to which they areattached to form a 5- to 7-membered monocyclic aromatic or nonaromaticring system having 0, 1, 2, 3, or 4 heteroatoms selected from the groupconsisting of N, O, and S wherein the ring nitrogen atoms areunsubstituted or substituted with one R¹ substituent and the ring carbonatoms are unsubstituted or substituted with one or two R¹ substituents,

and wherein any of the alkyl groups of R¹⁰, R¹¹, R¹², and R¹³ are eitherunsubstituted or substituted with one to three R¹ substituents;

wherein

each m is independently an integer from 0 to 6;

each n is independently an integer from 0 to 6

each p is independently an integer from 0 to 2;

each r is independently an integer from 1 to 3;

each s is independently an integer from 0 to 3;

each t is independently an integer from 0 to 3; and

each v is independently an integer from 0 to 2;

and the pharmaceutically acceptable salts thereof.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier.

The present invention also relates to methods for making thepharmaceutical compositions of the present invention.

The present invention also relates to methods for eliciting an integrinreceptor antagonizing effect in a mammal in need thereof byadministering the compounds and pharmaceutical compositions of thepresent invention.

The present invention also relates to methods for inhibiting boneresorption, restenosis, atherosclerosis, inflammation, inflammatoryarthritis, viral disease, diabetic retinopathy, macular degeneration,angiogenesis, and tumor growth and metastasis by administering thecompounds and pharmaceutical compositions of the present invention.

The present invention also relates to methods for treating osteoporosisby administering the compounds and pharmaceutical compositions of thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds useful as integrin receptorantagonists. Compounds of the present invention are described by thefollowing structural formulas selected from the group consisting of##STR3## wherein the dotted line a represents a single or a double bond,provided that when a represents a double bond, the double bond carbonatoms are substituted only with R¹⁰ and R¹² ;

X is selected from the group consisting of ##STR4## a 5- or 6-memberedmonocyclic aromatic or nonaromatic ring system having 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O, and S whereinthe ring nitrogen atoms are unsubstituted or substituted with one R¹substituent and the ring carbon atoms are unsubstituted or substitutedwith one or two R¹ substituents, and

a 9- to 14-membered polycyclic ring system, wherein one or more of therings is aromatic, and wherein the polycyclic ring system has 1, 2, 3 or4 heteroatoms selected from the group consisting of N, O, and S whereinthe ring nitrogen atoms are unsubstituted or substituted with one R¹substituent and the ring carbon atoms are unsubstituted or substitutedwith one or two R¹ substituents;

Y is selected from the group consisting of

--(CH₂)_(m) --,

--(CH₂)_(m) --O--(CH₂)_(n) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --,

--(CH₂)_(m) --S--(CH₂)_(n) --,

--(CH₂)_(m) --SO--(CH₂)_(n) --,

--(CH₂)_(m) --SO₂ --(CH₂)_(n) --,

--(CH₂)_(m) --O--(CH₂)_(n) --O--(CH₂)_(p) --,

--(CH₂)_(m) --O--(CH₂)_(n) --NR⁴ --(CH₂)_(p) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --NR⁴ --(CH₂)_(p) --,

--(CH₂)_(m) --O--(CH₂)_(n) --S--(CH₂)_(p) --,

--(CH₂)_(m) --S--(CH₂)_(n) --S--(CH₂)_(p) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --S--(CH₂)_(p) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --O--(CH₂)_(p) --,

--(CH₂)_(m) --S--(CH₂)_(n) --O--(CH₂)_(p) --,

--(CH₂)_(m) --S--(CH₂)_(n) --NR⁴ --(CH₂)_(p) --, and

--(CH₂)_(m) --Z--(CH₂)_(n) --,

wherein Z is a 3- to 10-membered monocyclic or polycyclic aromatic ornonaromatic ring system having 0, 1, 2, 3, or 4 heteroatoms selectedfrom the group consisting of N, O, and S wherein the ring nitrogen atomsare unsubstituted or substituted with one R¹ substituent and the ringcarbon atoms are unsubstituted or substituted with one or two R¹substituents, and wherein any methylene (CH₂) carbon atom in Y, otherthan in R⁴, can be substituted by one or two R³ substituents; and

wherein R¹ and R² are each independently selected from the groupconsisting of

hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl,C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkyl C₁₋₆ alkyl, aryl, arylC₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₈alkyl, (C₁₋₆ alkyl)_(p) amino, (C₁₋₆ alkyl)_(p) amino C₁₋₈ alkyl, C₁₋₄alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl,hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, C₁₋₆alkyloxy-C₁₋₆ alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy,trifluoroethoxy, C₁₋₈ alkyl-S(O)_(p), (C₁₋₈ alkyl)_(p) aminocarbonyl,C₁₋₈ alkyloxycarbonylamino, (C₁₋₈ alkyl)_(p) aminocarbonyloxy, (arylC₁₋₈ alkyl)_(p) amino, (aryl)_(p) amino, aryl C₁₋₈ alkylsulfonylamino,and C₁₋₈ alkylsulfonylamino;

or two R¹ substituents, when on the same carbon atom, are taken togetherwith the carbon atom to which they are attached to form a carbonylgroup;

each R³ is independently selected from the group consisting of

hydrogen,

aryl,

C₁₋₁₀ alkyl,

aryl-(CH₂)_(r) --O--(CH₂)_(s) --,

aryl-(CH₂)_(r) S(O)_(p) --(CH₂)_(s) --,

aryl-(CH₂)_(r) --C(O)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --N(R⁴)--C(o)--(CH₂)_(s) --,

aryl-(CH₂)_(r) N(R⁴)--(CH₂)_(s) --,

halogen,

hydroxyl,

oxo,

trifluoromethyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

(C₁₋₆ alkyl)_(p) amino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl;

or two R³ substituents, when on the same carbon atom, are taken togetherwith the carbon atom to which they are attached to form a carbonyl groupor a cyclopropyl group,

wherein any of the alkyl groups of R³ are either unsubstituted orsubstituted with one to three R¹ substituents, and provided that each R³is selected such that in the resultant compound the carbon atom or atomsto which R³ is attached is itself attached to no more than oneheteroatom;

each R⁴ is independently selected from the group consisting of

hydrogen,

aryl,

aminocarbonyl,

C₃₋₈ cycloalkyl,

amino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl,

(aryl C₁₋₅ alkyl)_(p) aminocarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

C₁₋₈ alkyl,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,

C₁₋₈ alkylsulfonyl,

C₁₋₈ alkoxycarbonyl,

aryloxycarbonyl,

aryl C₁₋₈ alkoxycarbonyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

aryl C₁₋₆ alkylcarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

aminosulfonyl,

C₁₋₈ alkylaminosulfonyl,

(aryl)_(p) aminosulfonyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonyl,

arylsulfonyl,

aryl-C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylthiocarbonyl,

arylthiocarbonyl, and

aryl C₁₋₆ alkylthiocarbonyl,

wherein any of the alkyl groups of R⁴ are either unsubstituted orsubstituted with one to three R¹ substituents;

R⁵ and R⁶ are each independently selected from the group consisting of

hydrogen,

C₁₋₁₀ alkyl,

aryl,

aryl-(CH₂)_(r) --O--(CH₂)_(s) --,

aryl-(CH₂)_(r) S(O)_(p) --(CH₂)_(s) --,

aryl-(CH₂)_(r) --C(O)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --,

halogen,

hydroxyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

(C₁₋₆ alkyl)_(p) amino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl C -8 alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl;

or R⁵ and R⁶ are taken together with the carbon atom to which they areattached to form a carbonyl group,

wherein any of the alkyl groups of R⁵ or R⁶ are either unsubstituted orsubstituted with one to three R¹ substituents,

and provided that each R⁵ and R⁶ are selected such that in the resultantcompound the carbon atom to which R⁵ and R⁶ are attached is itselfattached to no more than one heteroatom;

R⁷ and R⁸ are each independently selected from the group consisting of

hydrogen,

C₁₋₁₀ alkyl,

aryl,

aryl-(CH₂)_(r) --O--(CH₂)_(s) --,

aryl-(CH₂)_(r) S(O)_(p) --(CH₂)_(s) --,

aryl-(CH₂)_(r) --C(O)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --,

halogen,

hydroxyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

(C₁₋₆ alkyl)_(p) amino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylcarbonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

arylaminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl, and

C₇₋₂₀ polycyclyl C₀₋₈ alkylsulfonylamino;

wherein any of the alkyl groups of R⁷ and R⁸ are either unsubstituted orsubstituted with one to three R¹ substituents,

and provided that each R⁷ and R⁸ are selected such that in the resultantcompound the carbon atom to which R⁷ and R⁸ are attached is itselfattached to no more than one heteroatom;

R⁹ is selected from the group consisting of

hydrogen,

C₁₋₈ alkyl,

aryl,

aryl C₁₋₈ alkyl,

C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

C₁₋₈ alkylaminocarbonylmethylene, and

C₁₋₈ dialkylaminocarbonylmethylene;

R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from the groupconsisting of

hydrogen,

C₁₋₈ alkyl,

aryl,

halogen,

hydroxyl,

aminocarbonyl,

C₃₋₈ cycloalkyl,

amino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl,

hydroxycarbonyl,

(aryl C₁₋₅ alkyl)_(p) aminocarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,

C₁₋₈ alkylsulfonyl,

C₁₋₈ alkoxycarbonyl,

aryloxycarbonyl,

aryl C₁₋₈ alkoxycarbonyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

aryl C₁₋₆ alkylcarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

aminosulfonyl,

C₁₋₈ alkylaminosulfonyl,

(aryl)_(p) aminosulfonyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfony,

C₁₋₆ alkylsulfonyl,

arylsulfonyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylthiocarbonyl,

arylthiocarbonyl,

aryl C₁₋₆ alkylthiocarbonyl,

aryl-(CH₂)_(r) --O--(CH₂)_(s) --,

aryl-(CH₂)_(r) S(O)_(p) --(CH₂)_(s) --,

aryl-(CH₂)_(r) --C(O)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --,

aryl-(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) amino,

aminocarbonyl C₁₋₆ alkyl,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl; or

R¹⁰ and R¹² are taken together with the carbon atoms to which they areattached to form a 5- to 7-membered monocyclic aromatic or nonaromaticring system having 0, 1, 2, 3, or 4 heteroatoms selected from the groupconsisting of N, O, and S wherein the ring nitrogen atoms areunsubstituted or substituted with one R¹ substituent and the ring carbonatoms are unsubstituted or substituted with one or two R¹ substituents,

and wherein any of the alkyl groups of R¹⁰, R¹¹, R¹², and R¹³ are eitherunsubstituted or substituted with one to three R¹ substituents;

wherein

each m is independently an integer from 0 to 6;

each n is independently an integer from 0 to 6

each p is independently an integer from 0 to 2;

each r is independently an integer from 1 to 3;

each s is independently an integer from 0 to 3;

each t is independently an integer from 0 to 3; and

each v is independently an integer from 0 to 2;

and the pharmaceutically acceptable salts thereof.

In one embodiment of the present invention, compounds are described bythe following structural formulas selected from the group consisting of##STR5## wherein the dotted line a represents a single or a double bond,provided that when a represents a double bond, the double bond carbonatoms are substituted only with R¹⁰ and R¹².

In a class of this embodiment of the present invention, compounds aredescribed by the following structural formula ##STR6## wherein thedotted line a represents a single or a double bond, provided that when arepresents a double bond, the double bond carbon atoms are substitutedonly with R¹ and R¹².

In a subclass of this class of the present invention, compounds aredescribed by the following structural formula ##STR7##

In the compounds of the present invention, X is preferably a 6-memberedmonocyclic aromatic ring system having 1 or 2 nitrogen atoms whereineach ring carbon atom is unsubstituted or substituted with one R¹substituent, or

a 9- to 14-membered polycyclic ring system, wherein one or more of therings is aromatic, and wherein the polycyclic ring system has 1, 2, 3 or4 heteroatoms selected from the group consisting of N, O, and S whereinthe ring nitrogen atoms are unsubstituted or substituted with one R¹substituent and the ring carbon atoms are unsubstituted or substitutedwith one or two R¹ substituents.

More preferably, X is selected from the group consisting of ##STR8##

Most preferably X is ##STR9##

In the compounds of the present invention, Y is preferably selected fromthe group consisting of

--(CH₂)_(m) --,

--(CH₂)_(m) --O--(CH₂)_(n) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --,

--(CH₂)_(m) --S--(CH₂)_(n) --,

--(CH₂)_(m) --SO--(CH₂)_(n) --,

--(CH₂)_(m) --SO₂ --(CH₂)_(n) --,

--(CH₂)_(m) --O--(CH₂)_(n) --O--(CH₂)_(p) --,

--(CH₂)_(m) --O--(CH₂)_(n) --NR⁴ --(CH₂)_(p) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --NR⁴ --(CH₂)_(p) --, and

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --O--(CH₂)_(p) --,

wherein any methylene (CH₂) carbon atom in Y, other than in R⁴, can besubstituted by one or two R³ substituents.

More preferably Y is selected from the group consisting of

(CH₂)_(m), (CH₂)_(m) --S--(CH₂)_(n), (CH₂)_(m) --O--(CH₂)_(n), and(CH₂)_(m) --NR⁴ --(CH₂)_(n),

wherein any methylene (CH₂) carbon atom in Y, other than in R⁴, can besubstituted by one or two R³ substituents.

Most preferably Y is (CH₂)_(m) or (CH₂)_(m) --NR⁴ --(CH₂)_(n) whereinany methylene (CH₂) carbon atom in Y, other than R⁴, can be substitutedby one or two R³ substituents.

In the compounds of the present invention, R¹ and R² are preferablyselected from the group consisting of hydrogen, halogen, C₁₋₁₀ alkyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl, hydroxy, nitro, cyano,trifluoromethyl, and trifluoromethoxy.

More preferably, R¹ and R² are selected from the group consisting ofhydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, trifluoromethyl, andtrifluoromethoxy.

In the compounds of the present invention, R³ is preferably selectedfrom the group consisting of

hydrogen,

fluoro,

trifluoromethyl,

aryl,

C₁₋₈ alkyl,

aryl-C₁₋₆ alkyl

hydroxyl,

oxo,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl, and

aminocarbonyl C₁₋₆ alkyl.

More preferably, R³ is selected from the group consisting of

fluoro,

aryl,

C₁₋₈ alkyl,

aryl-C₁₋₆ alkyl

hydroxyl,

oxo, and

arylaminocarbonyl.

In the compounds of the present invention, R⁴ is preferably selectedfrom the group consisting of

hydrogen,

aryl,

C₃₋₈ cycloalkyl,

C₁₋₈ alkyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

C₁₋₆ alkylsulfonyl,

arylsulfonyl,

aryl C₁₋₆ alkylsulfonyl,

aryl-C₁₋₆ alkylcarbonyl,

C₁₋₈ alkylaminocarbonyl,

aryl-C₁₋₅ alkylaminocarbonyl,

aryl-C₁₋₈ alkoxycarbonyl, and

C₁₋₈ alkoxycarbonyl.

More preferably, R⁴ is selected from the group consisting of

hydrogen,

C₁₋₈ alkyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

arylC₁₋₆ alkylcarbonyl,

C₁₋₆ alkylsulfonyl,

arylsulfonyl, and

aryl-C₁₋₆ alkylsulfonyl.

In one embodiment of the present invention, R⁵ and R⁶ are eachindependently selected from the group consisting of

hydrogen,

aryl,

C₁₋₈ alkyl,

aryl-C.tbd.C--(CH₂)_(t) --,

aryl C₁₋₆ alkyl,

CH₂ ═CH--(CH₂)_(t) --, and

HC.tbd.C--(CH₂)_(t) --.

In a class of this embodiment of the present invention, R⁶ is hydrogenand R⁵ is selected from the group consisting of

hydrogen,

aryl,

C₁₋₈ alkyl,

aryl-C.tbd.C--(CH₂)_(t) --,

aryl C₁₋₆ alkyl,

CH₂ ═CH--(CH₂)_(t) --, and

HC.tbd.C--(CH₂)_(t) --.

In a subclass of this class of the present invention, R⁶, R⁷, and R⁸ areeach hydrogen and R⁵ is selected from the group consisting of

hydrogen,

aryl,

C₁₋₈ alkyl,

aryl-C.tbd.C--(CH₂)_(t) --,

aryl C₁₋₆ alkyl,

CH₂ ═CH--(CH₂)_(t) --, and

HC.tbd.C--(CH₂)_(t) --,

In another embodiment of the present invention, R⁷ and R⁸ are eachindependently selected from the group consisting of

hydrogen,

aryl,

C₁₋₈ alkylcarbonylamino,

arylcarbonylamino,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino, and

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl.

In a class of this embodiment of the present invention, R⁸ is hydrogenand R⁷ is selected from the group consisting of consisting of

hydrogen,

aryl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino,

arylcarbonylamino,

C₁₋₈ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino,

arylaminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino, and

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino.

In a subclass of this class of the present invention, R⁵, R⁶, and R⁸ areeach hydrogen and R⁷ is selected from the group consisting of

hydrogen,

aryl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino,

arylcarbonylamino,

C₁₋₈ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino,

arylaminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino, and

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino.

In the compounds of the present invention, R⁹ is preferably selectedfrom the group consisting of hydrogen, methyl, and ethyl.

More preferably, R⁹ is hydrogen.

In the compounds of the present invention, R¹⁰, R¹¹, R¹², and R¹³ arepreferably each independently selected from the group consisting ofhydrogen, aryl, C₁₋₆ alkyl, and aryl-C₁₋₆ alkyl.

In the compounds of the present invention, m is preferably an integerfrom 0 to 4, and more preferably from 0 to 3.

In the compounds of the present invention, n is preferably an integerfrom 0 to 4, more preferably from 0 to 3.

In the compounds of the present invention, r is preferably an integerfrom 1 to 2.

In the compounds of the present invention, s is preferably an integerfrom 0 to 2.

In the compounds of the present invention, t is preferably an integerfrom 0 to 2, more preferably from 0 to 1.

In the compounds of the present invention, v is preferably 0.

In certain embodiments of the present invention, the compoundscorrespond to the formulas with the following designated stereochemistryat the carbon atom where R⁵ and R⁶ are attached: ##STR10## wherein thesubstituents X, Y, Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,and R¹³ and the subscripts a, m, n, p, r, s, t, and v are as describedabove.

Illustrative but nonlimiting examples of compounds of the instantinvention that are useful as integrin receptor antagonists are thefollowing:

3(R)-(3-fluoro-phenyl)-3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3(R)-yl}-propionicacid,

3(R)-(3-fluoro-phenyl)-3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3(S)-yl}-propionicacid,

3(S)-(3-fluoro-phenyl)-3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3(R)-yl}-propionicacid,

3(S)-(3-fluoro-phenyl)-3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3(S)-yl}-propionicacid,

3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl}-3(R)-quinolin-3(R)-yl-propionicacid,

3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl}-3(R)-quinolin-3(S)-yl-propionicacid,

3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyrdin-2-yl)-propyl]-pyrrolidin-3-yl}-3-(S)-quinolin-3(R)-yl-propionicacid,

3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl}-3(S)-quinolin-3(S)-yl-propionicacid,

and the pharmaceutically acceptable salts thereof.

For use in medicine, the salts of the compounds of this invention referto non-toxic "pharmaceutically acceptable salts." Other salts may,however, be useful in the preparation of the compounds according to theinvention or of their pharmaceutically acceptable salts. Saltsencompassed within the term "pharmaceutically acceptable salts" refer tonon-toxic s alts of the compounds of this invention which ar e generallyprepared by reacting the free base with a suitable organic or inorganicacid. Representative salts include the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts.

The compounds of the present invention can have chiral centers and occuras racemates, racemic mixtures, diastereomeric mixtures, and asindividual diastereomers, or enantiomers with all isomeric forms beingincluded in the present invention. Therefore, where a compound ischiral, the separate enantiomers or diastereomers, substantially free ofthe other, are included within the scope of the invention; furtherincluded are all mixtures of the two enantiomers. Also included withinthe scope of the invention are polymorphs and hydrates of the compoundsof the instant invention.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertiblein viuo into the required compound. Thus, in themethods of treatment of the present invention, the term "administering"shall encompass the treatment of the various conditions described withthe compound specifically disclosed or with a compound which may not bespecifically disclosed, but which converts to the specified compound invivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in "Design of Prodrugs," ed. H. Bundgaard,Elsevier, 1985, which is incorporated by reference herein in itsentirety. Metabolites of these compounds include active species producedupon introduction of compounds of this invention into the biologicalmilieu.

The term "therapeutically effective amount" shall mean that amount of adrug or pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought by aresearcher or clinician.

The term "integrin receptor antagonist," as used herein, refers to acompound which binds to and antagonizes either the ανβ3 receptor, theανβ5 receptor, or the ανβ6 receptor, or a compound which binds to andantagonizes combinations of these receptors (for example, a dualανβ3/ανβ5 receptor antagonist).

The term "bone resorption," as used herein, refers to the process bywhich osteoclasts degrade bone.

The term "alkyl" shall mean straight or branched chain alkanes of one toten total carbon atoms, or any number within this range (i.e., methyl,ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).

The term "alkenyl" shall mean straight or branched chain alkenes of twoto ten total carbon atoms, or any number within this range.

The term "alkynyl" shall mean straight or branched chain alkynes of twoto ten total carbon atoms, or any number within this range.

The term "cycloalkyl" shall mean cyclic rings of alkanes of three toeight total carbon atoms, or any number within this range (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl).

The term "cycloheteroalkyl," as used herein, shall mean a 3- to8-membered fully saturated heterocyclic ring containing one or twoheteroatoms chosen from N, O or S. Examples of cycloheteroalkyl groupsinclude, but are not limited to piperidinyl, pyrrolidinyl, azetidinyl,morpholinyl, piperazinyl.

The term "alkoxy," as used herein, refers to straight or branched chainalkoxides of the number of carbon atoms specified (e.g., C₁₋₅ alkoxy),or any number within this range (i.e., methoxy, ethoxy, etc.).

The term "aryl," as used herein, refers to a monocyclic or polycyclicsystem comprising at least one aromatic ring, wherein the monocylic orpolycyclic system contains 0, 1, 2, 3, or 4 heteroatoms chosen from N,O, or S, and wherein the monocylic or polycylic system is eitherunsubstituted or substituted with one or more groups independentlyselected from hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, aryl,aryl C₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃ acylamino, C₁₋₃ acylaminoC₁₋₈ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkylamino C₁₋₈ alkyl, C₁₋₆dialkylamino, C₁₋₆ dialkylamino-C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxyC₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl, C₁₋₅alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl, hydroxycarbonyl C₁₋₆alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, cyano, trifluoromethyl, oxo orC₁₋₅ alkylcarbonyloxy. Examples of aryl include, but are not limited to,phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, imidazolyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, indolyl, thienyl, furyl,pyrryl, pyrazolyl, dihydrobenzofuryl, benzo(1,3) dioxolane, oxazolyl,isoxazolyl and thiazolyl, which are either unsubstituted or substitutedwith one or more groups independently selected from hydrogen, halogen,C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, aryl, aryl C₁₋₈ alkyl, amino, amino C₁₋₈alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₈ alkyl, C₁₋₆ alkylamino, C₁₋₆alkylamino-C₁₋₈ alkyl, C₁₋₆ dialkylamino, C₁₋₆ dialkylamino C₁₋₈ alkyl,C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonylC₁₋₆ alkyl, C₁₋₅ alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl,hydroxycarbonyl C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, cyano,trifluoromethyl, oxo or C₁₋₅ alkylcarbonyloxy. Preferably, the arylgroup is unsubstituted, mono-, di-, tri- or tetra-substituted with oneto four of the above-named substituents; more preferably, the aryl groupis unsubstituted, mono-, di- or tri-substituted with one to three of theabove-named substituents; most preferably, the aryl group isunsubstituted, mono- or di-substituted with one to two of theabove-named substituents.

Whenever the term "alkyl" or "aryl" or either of their prefix rootsappears in a name of a substituent (e.g., aryl C₀₋₈ alkyl), it shall beinterpreted as including those limitations given above for "alkyl" and"aryl." Designated numbers of carbon atoms (e.g., C₁₋₁₀) shall referindependently to the number of carbon atoms in an alkyl or cyclic alkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

The terms "arylalkyl" and "alkylaryl" include an alkyl portion wherealkyl is as defined above and to include an aryl portion where aryl isas defined above. Examples of arylalkyl include, but are not limited to,benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl,fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, andthienylpropyl. Examples of alkylaryl include, but are not limited to,toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine,propylpyridine and butylpyridine.

In the compounds of the present invention, two R¹ substituents, when onthe same carbon atom, can be taken together with the carbon to whichthey are attached to form a carbonyl group.

In the compounds of the present invention, two R³ substituents, when onthe same carbon atom, can be taken together with the carbon atom towhich they are attached to form a carbonyl group. In such instances, thelimitation, that in the resultant compound the carbon atom or atoms towhich R³ is attached is itself attached to no more than one heteroatom,does not apply. Also, in the compounds of the present invention, two R³substituents, when on the same carbon atom, can be taken together withthe carbon atom to which they are attached to form a cyclopropyl group.

In the compounds of the present invention, R⁵ and R⁶ can be takentogether with the carbon atom to which they are attached to form acarbonyl group. In such instances, the limitation, that in the resultantcompound the carbon atom at which R⁵ and R⁶ is attached is itselfattached to no more than one heteroatom, does not apply.

When substituents R⁷ and R⁸ include the definition C₀ (e.g., C₀₋₈alkyl), the group modified by C₀ is not present in the substituent whenC is zero. Similarly, when any of the variables m, n, t, or v, is zero,then the group modified by the variable is not present; for example,when t is zero, the group "--(CH₂)_(t) C.tbd.CH" is "--C.tbd.CH". Inaddition, the substituent "(C₁₋₆ alkyl)_(p) amino" where p is zero, oneor two, refers to an amino, C₁₋₆ alkylamino and C₁₋₆ dialkylamino group,respectively. When a C₁₋₆ dialkylamino substituent is intended, the C₁₋₆alkyl groups can be the same (e.g., dimethylamino) or different (e.g.,N(CH₃)(CH₂ CH₃)). Similarly, the substituent "(aryl)_(p) amino" or["(aryl C₁₋₆ alkyl)_(p) amino"], where p is zero, one or two, refers toan amino, arylamino and diarylamino group, [or an amino, aryl C₁₋₆alkylamino or di-(aryl C₁₋₆ alkyl)amino] respectively, where the aryl[or aryl C₁₋₆ alkyl] groups in a diarylamino [or di-(aryl C₁₋₆alkyl)amino] substituent can be the same or different.

In the compounds of the present invention, R¹⁰ and R¹² can be takentogether with the carbon atoms to which they are attached to form a 5-to 7-membered monocyclic aromatic or nonaromatic ring system having 0,1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O,and S wherein said 5- to 7-membered monocylic aromatic or nonaromaticring system is either unsubstituted or substituted with one or more R¹substituents.

The term "halogen" shall include iodine, bromine, chlorine, andfluorine.

The term "oxy" means an oxygen (O) atom. The term "thio" means a sulfur(S) atom. The term "oxo" means "═O." The term "carbonyl" means "C═O."

The term "substituted" shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

Under standard nonmenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to ##STR11##

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. X, Y, Z, R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ and thesubscripts m, n, p, r, s, t, and v are to be chosen in conformity withwell-known principles of chemical structure connectivity.

Representative compounds of the present invention typically displaysubmicromolar affinity for the integrin receptors, particularly theανβ3, ανβ5, and/or ανβ6 receptors. Compounds of this invention aretherefore useful for treating mammals suffering from a bone conditioncaused or mediated by increased bone resorption, who are in need of suchtherapy. Pharmacologically effective amounts of the compounds, includingpharamaceutically acceptable salts thereof, are administered to themammal, to inhibit the activity of mammalian osteoclasts.

The compounds of the present invention are administered in dosageseffective to antagonize the ανβ3 receptor where such treatment isneeded, as, for example, in the prevention or treatment of osteoporosis.

Further exemplifying the invention is the method wherein the integrinreceptor antagonizing effect is an ανβ3 antagonizing effect. Anillustration of the invention is the method wherein the ανβ3antagonizing effect is selected from inhibition of bone resorption,restenosis, angiogenesis, diabetic retinopathy, macular degeneration,inflammation, viral disease, tumor growth, or metastasis. Preferably,the ανβ3 antagonizing effect is the inhibition of bone resorption.

An example of the invention is the method wherein the integrin receptorantagonizing effect is an ανβ5 antagonizing effect. More specifically,the ανβ5 antagonizing effect is selected from inhibition of restenosis,angiogenesis, diabetic retinopathy, macular degeneration, inflammation,tumor growth, or metastasis.

Illustrating the invention is the method wherein the integrin receptorantagonizing effect is a dual ανβ3/ανβ5 antagonizing effect. Moreparticularly, the dual ανβ3/ανβ5 antagonizing effect is selected frominhibition of bone resorption, restenosis, angiogenesis, diabeticretinopathy, macular degeneration, inflammation, viral disease, tumorgrowth, or metastasis.

Illustrating the invention is the method wherein the integrin receptorantagonizing effect is an ανβ6 antagonizing effect. More particularly,the ανβ6 antagonizing effect is selected from inhibition ofangiogenesis, inflammatory response, or wound healing.

Illustrating the invention is the method wherein the ανβ3 antagonizingeffect is selected from inhibition of bone resorption, inhibition ofrestenosis, inhibition of angiogenesis, inhibition of diabeticretinopathy, inhibition of macular degeneration, inhibition ofatherosclerosis, inflammation, viral disease, or inhibition of tumorgrowth or metastasis. Preferably, the ανβ3 antagonizing effect is theinhibition of bone resorption.

More particularly illustrating the invention is a pharmaceuticalcomposition comprising any of the compounds described above and apharmaceutically acceptable carrier. Another example of the invention isa pharmaceutical composition made by combining any of the compoundsdescribed above and a pharmaceutically acceptable carrier. Anotherillustration of the invention is a process for making a pharmaceuticalcomposition comprising combining any of the compounds described aboveand a pharmaceutically acceptable carrier.

Further illustrating the invention is a method of treating and/orpreventing a condition mediated by antagonism of an integrin receptor ina mammal in need thereof, comprising administering to the mammal atherapeutically effective amount of any of the compounds describedabove. Preferably, the condition is selected from bone resorption,osteoporosis, restenosis, diabetic retinopathy, macular degeneration,angiogenesis, atherosclerosis, inflammation, viral disease, cancer,tumor growth, and metastasis. More preferably, the condition is selectedfrom osteoporosis and cancer. Most preferably, the condition isosteoporosis.

More specifically exemplifying the invention is a method of eliciting anintegrin antagonizing effect in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of any ofthe compounds or any of the pharmaceutical compositions described above.Preferably, the integrin antagonizing effect is an ανβ3 antagonizingeffect; more specifically, the ανβ3 antagonizing effect is selected frominhibition of bone resorption, inhibition of restenosis, inhibition ofatherosclerosis, inhibition of angiogenesis, inhibition of diabeticretinopathy, inhibition of macular degeneration, inhibition ofinflammation, inhibition of viral disease, or inhibition of tumor growthor metastasis. Most preferably, the ανβ3 antagonizing effect isinhibition of bone resorption. Alternatively, the integrin antagonizingeffect is an ανβ5 antagonizing effect, an ανβ6 antagonizing effect, or amixed ανβ3, ανβ5, and ανβ6 antagonizing effect. Examples of ανβ5antagonizing effects are inhibition of restenosis, atherosclerosis,angiogenesis, diabetic retinopathy, macular degeneration, inflammation,viral disease, or tumor growth. Examples of dual ανβ6 antagonizingeffects are inhibition of angiogenesis, inflammatory response and woundhealing.

Additional examples of the invention are methods of inhibiting boneresorption and of treating and/or preventing osteoporosis in a mammal inneed thereof, comprising administering to the mammal a therapeuticallyeffective amount of any of the compounds or any of the pharmaceuticalcompositions described above.

Additional illustrations of the invention are methods of treatinghypercalcemia of malignancy, osteopenia due to bone metastases,periodontal disease, hyperparathyroidism, periarticular erosions inrheumatoid arthritis, Paget's disease, immobilizationinduced osteopenia,and glucocorticoid treatment in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of any ofthe compounds or any of the pharmaceutical compositions described above.

More particularly exemplifying the invention is the use of any of thecompounds described above in the preparation of a medicament for thetreatment and/or prevention of osteoporosis in a mammal in need thereof.Still further exemplifying the invention is the use of any of thecompounds described above in the preparation of a medicament for thetreatment and/or prevention of bone resorption, tumor growth, cancer,restenosis, atherosclerosis, diabetic retinopathy, macular degeneration,inflammation, viral disease, and/or angiogenesis.

Also exemplifying the invention are compositions further comprising anactive ingredient selected from the group consisting of

a) an organic bisphosphonate or a pharmaceutically acceptable salt orester thereof,

b) an estrogen receptor modulator,

c) a cytotoxic/antiproliferative agent,

d) a matrix metalloproteinase inhibitor,

e) an inhibitor of epidermal-derived, fibroblast-derived, orplatelet-derived growth factors,

f) an inhibitor of VEGF,

g) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1,

h) a cathepsin K inhibitor,

i) an inhibitor of osteoclast proton ATPase, and

j) a prenylation inhibitor, such as a farnesyl transferase inhibitor ora geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyltransferase inhibitor;

and mixtures thereof.

(See, B. Millauer et al., "Dominant-Negative Inhibition of Flk-1Suppresses the Growth of Many Tumor Types in Vivo", Cancer Research, 56,1615-1620 (1996), which is incorporated by reference herein in itsentirety).

Preferably, the active ingredient is selected from the group consistingof:

a) an organic bisphosphonate or a pharmaceutically acceptable salt orester thereof,

b) an estrogen receptor modulator,

c) an inhibitor of osteoclast proton ATPase, and

d) a cathepsin K inhibitor; and mixtures thereof.

Nonlimiting examples of such bisphosphonates include alendronate,etidronate, pamidronate, risedronate, ibandronate, and pharmaceuticallyacceptable salts and esters thereof. A particularly preferredbisphosphonate is alendronate, especially alendronate monosodiumtrihydrate.

Nonlimiting examples of estrogen receptor modulators include estrogen,progesterin, estradiol, droloxifene, raloxifene, and tamoxifene.

Nonlimiting examples of cytotoxic/antiproliferative agents are taxol,vincristine, vinblastine, and doxorubicin.

Cathepsin K, formerly known as cathepsin O2, is a cysteine protease andis described in PCT International Application Publication No. WO96/13523, published May 9, 1996; U.S. Pat. No. 5,501,969, issued Mar. 3,1996; and U.S. Pat. No. 5,736,357, issued Apr. 7, 1998, all of which areincorporated by reference herein in their entirety. Cysteine proteases,specifically cathepsins, are linked to a number of disease conditions,such as tumor metastasis, inflammation, arthritis, and bone remodeling.At acidic pH's, cathepsins can degrade type-I collagen. Cathepsinprotease inhibitors can inhibit osteoclastic bone resorption byinhibiting the degradation of collagen fibers and are thus useful in thetreatment of bone resorption diseases, such as osteoporosis.

The proton ATPase which is found on the apical membrane of theosteoclast has been reported to play a significant role in the boneresorption process. Therefore, this proton pump represents an attractivetarget for the design of inhibitors of bone resorption which arepotentially useful for the treatment and prevention of osteoporosis andrelated metabolic diseases (see C. Farina et al., "Selective inhibitorsof the osteoclast vacuolar proton ATPase as novel bone antiresorptiveagents," DDT, 4: 163-172 (1999)).

The present invention is also directed to combinations of the compoundsof the present invention with one or more agents useful in theprevention or treatment of osteoporosis. For example, the compounds ofthe instant invention may be effectively administered in combinationwith effective amounts of other agents such as an organicbisphosphonate, an estrogen receptor modulator, or a cathepsin Kinhibitor.

Additional illustrations of the invention are methods of treating tumorgrowth in a mammal in need thereof, comprising administering to themammal a therapeutically effective amount of a compound described aboveand one or more agents known to be cytotoxic/antiproliferative. Also,the compounds of the present invention can be administered incombination with radiation therapy for treating tumor growth andmetastasis.

In addition, the integrin ανβ3 antagonist compounds of the presentinvention may be effectively administered in combination with a growthhormone secretagogue in the therapeutic or prophylactic treatment ofdisorders in calcium or phosphate metabolism and associated diseases.These diseases include conditions which can benefit from a reduction inbone resorption. A reduction in bone resorption should improve thebalance between resorption and formation, reduce bone loss or result inbone augmentation. A reduction in bone resorption can alleviate the painassociated with osteolytic lesions and reduce the incidence and/orgrowth of those lesions. These diseases include: osteoporosis (includingestrogen deficiency, immobilization, glucocorticoid induced and senile),osteodystrophy, Paget's disease, myositis ossificans, Bechterew'sdisease, malignant hypercalcemia, metastatic bone disease, periodontaldisease, cholelithiasis, nephrolithiasis, urolithiasis, urinarycalculus, hardening of the arteries (sclerosis), arthritis, bursitis,neuritis and tetany. Increased bone resorption can be accompanied bypathologically high calcium and phosphate concentrations in the plasma,which would be alleviated by this treatment. Similarly, the presentinvention would be useful in increasing bone mass in patients withgrowth hormone deficiency. Thus, preferred combinations are simultaneousor alternating treatments of an ανβ3 receptor antagonist of the presentinvention and a growth hormone secretagogue, optionally including athird component comprising an organic bisphosphonate, preferablyalendronate monosodium trihydrate.

In accordance with the method of the present invention, the individualcomponents of the combination can be administered separately atdifferent times during the course of therapy or concurrently in dividedor single combination forms. The instant invention is therefore to beunderstood as embracing all such regimes of simultaneous or alternatingtreatment, and the term "administering" is to be interpretedaccordingly. It will be understood that the scope of combinations of thecompounds of this invention with other agents useful for treatingintegrin-mediated conditions includes in principle any combination withany pharmaceutical composition useful for treating osteoporosis.

As used herein, the term "composition" is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, topical (e.g., ocular eyedrop), subcutaneous,intramuscular or transdermal (e.g., patch) form, all using forms wellknown to those of ordinary skill in the pharmaceutical arts. Aneffective but non-toxic amount of the compound desired can be employedas an ανβ3 antagonist.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic finction of the patient; and the particularcompound or salt thereof employed. An ordinarily skilled physician,veterinarian or clinician can readily determine and prescribe theeffective amount of the drug required to prevent, counter or arrest theprogress of the condition.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.01 mg per kg of body weight per day(mg/kglday) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, andmost preferably 0.1 to 5.0 mg/kg/day. For oral administration, thecompositions are preferably provided in the form of tablets containing0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. A medicament typically containsfrom about 0.01 mg to about 500 mg of the active ingredient, preferably,from about 1 mg to about 100 mg of active ingredient. Intravenously, themost preferred doses will range from about 0.1 to about 10 mg/kg/minuteduring a constant rate infusion. Advantageously, compounds of thepresent invention may be administered in a single daily dose, or thetotal daily dosage may be administered in divided doses of two, three orfour times daily. Furthermore, preferred compounds for the presentinvention can be administered in intranasal form via topical use ofsuitable intranasal vehicles, or via transdermal routes, using thoseforms of transdermal skin patches well known to those of ordinary skillin the art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittent throughout the dosage regimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients orcarriers (collectively referred to herein as `carrier` materials)suitably selected with respect to the intended form of administration,that is, oral tablets, capsules, elixirs, syrups and the like, andconsistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Disintegratorsinclude, without limitation, starch, methyl cellulose, agar, bentonite,xanthan gum and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcrosslinked or amphipathic block copolymers of hydrogels.

In the schemes and examples below, various reagent symbols andabbreviations have the following meanings:

AcOH: Acetic acid.

BH₃ •DMS: Borane•dimethylsulfide.

BOC(Boc): t-Butyloxycarbonyl.

BOP: Benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate.

CBZ(Cbz): Carbobenzyloxy or benzyloxycarbonyl.

CDI: Carbonyldiimidazole.

CH₂ Cl₂ : Methylene chloride.

CH₃ CN: Acetonitrile

CHCl₃ : Chloroform.

DBA: Bis(dibenzylidene)acetone.

DEAD: Diethyl azodicarboxylate.

DIAD: Diisopropyl azodicarboxylate.

DIBAH or

DIBAL-H: Diisobutylaluminum hydride.

DIPEA: Diisopropylethylamine.

DMAP: 4-Dimethylaminopyridine.

DME: 1,2-Dimethoxyethane.

DMF: Dimethylformamide.

DMSO: Dimethylsulfoxide.

DPPF: 1,1'-bis(diphenylphosphino)ferrocene.

DPFN: 3,5-Dimethyl-1-pyrazolylformamidine nitrate.

EDC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide•HCl

EtOAc: Ethyl acetate.

EtOH: Ethanol.

HOAc: Acetic acid.

HOAT: 1-Hydroxy-7-azabenzotriazole

HOBT: 1-Hydroxybenzotriazole.

HPLC; High-performance liquid chromatography.

IBCF: Isobutylchloroformate

LDA: Lithium diisopropylamide.

MeOH: Methanol.

MMNG 1,1-methyl-3-nitro-1-nitrosoguanidine

NEt₃ : Triethylamine.

NMM: N-methylmorpholine.

PCA•HCl: Pyrazole carboxamidine hydrochloride.

Pd/C: Palladium on activated carbon catalyst.

Ph: Phenyl.

pTSA p-Toluenesulfonic acid.

TEA: Triethylamine.

TFA: Trifluoroacetic acid.

THF: Tetrahydrofuran.

TLC: Thin Layer Chromatography.

TMEDA: N,N,N',N'-Tetramethylethylenediamine.

TMS: Trimethylsilyl.

The novel compounds of the present invention can be prepared accordingto the procedure of the following schemes and examples, usingappropriate materials and are further exemplified by the followingspecific examples. The compounds illustrated in the examples are not,however, to be construed as forming the only genus that is considered asthe invention. The following examples further illustrate details for thepreparation of the compounds of the present invention. Those skilled inthe art will readily understand that known variations of the conditionsand processes of the following preparative procedures can be used toprepare these compounds. All temperatures are degrees Celsius unlessotherwise noted.

The following Schemes and Examples describe procedures for makingrepresentative compounds of the present invention. Moreover, byutilizing the procedures described in detail in PCT InternationalApplication Publication Nos. WO95/32710, published Dec. 7, 1995, andWO95/17397, published Jun. 29, 1995, both of which are incorporated byreference herein in their entirety, in conjunction with the disclosurecontained herein, one of ordinary skill in the art can readily prepareadditional compounds of the present invention claimed herein.Additionally, for a general review describing the synthesis ofβ-alanines which can be utilized as the C-terminus of the compounds ofthe present invention, see Cole, D. C., Recent Stereoselective SyntheticApproaces to β-Amino Acids, Tetrahedron, 1994, 50, 9517-9582; Juaristi,E, et al., Enantioselective Synthesis of β-Amino Acids, AldrichimicaActa, 1994, 27, 3. In particular, synthesis of the 3-methyl-β-alanine istaught in Duggan, M. F. et al., J. Med. Chem., 1995, 38, 3332-3341; the3-ethynyl-β-alanine is taught in Zablocki, J. A., et al., J. Med. Chem.,1995, 38, 2378-2394; the 3-(pyridin-3-yl)-β-alanine is taught in Rico,J. G. et al., J. Org. Chem., 1993, 58, 7948-7951; and the 2-amino- and2-tosylamino-β-alanines are taught in Xue, C-B, et al., Biorg. Med.Chem. Letts., 1996, 6, 339-344. The references described in thisparagraph are all also incorporated by reference herein in theirentirety. ##STR12##

[3-(N-Methoxy-N-methyl-carbamoyl)-propyl]carbamic acid tert-butyl ester(1-3)

A mixture of 1-1 (10 g, 49.2 mmol), 1-2 (4.8 mg, 49.2 mmol), EDC (9.40g, 49.2 mmol), HOBT (6.6 g, 49.2 mmol) and NMM (2.7 mL, 246 mmol) in CH₃CN (200 mL) was stirred for 20 h. The reaction was concentrated. Theresidue was dissolved in ethyl acetate, washed with H₂ O, 10% KHSO₄,sat. NaHCO₃, brine, and dried over MgSO₄. Evaporative removal of thesolvent gave 1-3 as a colorless oil. TLC R_(f) =0.15 (50% ethylacetate/hexanes).

¹ H NMR (300 MHz, CDCl₃) δ 4.96 (bs,1H), 3.55 (s, 3H), 3.46 (m, 5H),2.48 (t, J=7.3 Hz, 2H), 1.83 (m, 2H), 1.46 (s, 9H).

(4-Oxo-pentyl)carbamic acid tert-butyl ester (1-4)

To a stirred solution of 1-3 (10.0 g, 40.5 mmol) and THF (200 ml) at 0°C. was added methyl magnesium bromide (27.0 ml, 91.0 mmol; 3M in ether)dropwise over 20 minutes. Mter 2.0 hours, 10% KHSO₄ was added slowly.The mixture was extracted with EtOAc. The organic portion was washedwith saturated NaHCO₃, brine, and dried over MgSO₄. Evaporative removalof the solvent gave 1-4 as a colorless oil.

TLC R_(f) =0.53 (silica, 40% EtOAc/hexanes). ¹ H NMR (300 MHz, CDCl₃) δ4.62 (bs,1H), 3.13 (m, 2H), 2.49 (t, J=7.1 Hz, 2H), 2.16 (s, 3H), 1.78(m, 2H), 1.44 (s, 9H).

(3-[1,8]Naphthyridin-2-yl)-N-Boc-propylamine (1-6)

A mixture of 1-4 (5.0 g, 24.8 mmol), 2-amino-3-formylpyridine 1-5 [3.6g, 29.8 mmol; for preparation see J. Org. Chem., 48: 3401 (1983)] and20% KOH (1 ml) in absolute ethanol (100 mL) was heated at reflux for 8h. Following evaporative removal of the solvent, the residue waschromatographed (silica gel, 70:28:2 chloroform/ethyl acetate/methanol)to give 1-6 as a yellow oil.

TLC R_(f) =0.40 (silica, 70:20:10 chloroform/ethyl acetate/methanol). ¹H NMR (300 MHz, CDCl₃) δ 9.08 (m, 1H), 8.16 (d, J=8.1 Hz, 1H), 8.10 (d,J=8.1 Hz, 1H), 7.41 (m, 2H), 4.82 (bs, 1H), 3.21 (m, 2H), 3.06 (m, 2H),2.12 (m,2H), 1.43 (s, 9H).

3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-N-Boc-propylamine (1-7)

A mixture of 1-6 (4.0 g, 13.9 mmol) and 10% Pd/carbon (4.0 g) in EtOH(100 mL) was stirred under a balloon of hydrogen for 4 h. Followingfiltration and evaporative removal of the solvent, the residue waschromatographed (silica gel, 70:28:2 chloroform/ethyl acetate/methanol)to give 1-7 as a white solid.

TLC R_(f) =0.30 (silica, 70:25:5 chloroform/ethyl acetate/methanol). ¹ HNMR (300 MHz, CDCl₃) δ 7.05 (d, J=7.3 Hz, 1H), 6.34 (d, J=7.3 Hz, 1H),5.48 (s, 1H), 4.79 (s, 1H), 3.37 (m, 2H), 3.15 (m, 2H), 2.69 (t, J=6.3Hz, 2H), 2.59 (t, J=7.3 Hz, 2H), 1.88 (m, 4H), 1.44 (s, 9H).

3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-propylaminedihydrochloride (1-8)

HCl gas was rapidly bubbled through a solution of 1-7 (2.5 g, 8.6 mmol)in EtOAc (100 ml) at 0° C. for 10 minutes. After 30 minutes, thesolution was purged with argon for 30 minutes. The solution wasconcentrated and then azeotroped with CH₃ CN to give the amine 1-8 as ayellow solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.61 (d, J=7.3 Hz, 1H), 6.67 (d, J=7.3 Hz,1H), 3.52 (t, J=5.6 Hz, 2H), 2.99 (m, 2H), 2.83 (m, 4H), 2.08 (m,2H),1.96 (m, 2H). ##STR13##

2-Ethoxycarbonyl-3-(3-fluoro-phenyl)-pentanedioic acid diethyl ester(2-2)

To a suspension of NaH (1.59 g, 63.1 mmol) in 200 mL THF was addeddiethyl malonate (10.0 g, 62.4 mmol) gradually. The reaction mixture wasstirred for 1 hr at room temperature. 3-(3-Fluorophenyl)acrylic acidethyl ester (2-1) (11.1 g, 57.2 mmol; prepared via standard proceduresfrom 3-fluorocinnamic acid) and EtOH (5 mL) are added. The mixture wasthen stirred at 90° C. for 12 hr, concentrated under diminished pressureand treated with 50 mL 10% sodium hydrogencarbonate solution. Theaqueous mixture was extracted three times with ethyl acetate. Thecombined organic layers were washed with brine and dried (Na₂ SO₄).After solvent removal, the residue was purified using silica gel flashchromatography (6:1 hexane/EtOAc) to give 2-2 as an oil.

R_(f) (silica; hexane/EtOAc 6:1)=0.18.

3-(3-Fluoro-phenyl)-pentanedioic acid (2-3)

2-Ethoxycarbonyl-3-(3-fluoro-phenyl)-pentanedioic acid diethyl ester(2-2) (6.90 g, 19.5 mmol) was treated with 6 N HCl (150 mL). The mixturewas refluxed for 24 hr, poured into 200 mL ice-water and extracted withEtOAc (×3). The combined organic layers were washed with brine, dried(Na₂ SO₄) and concentrated to provide 2-3 as a solid which was used inthe next step without further purification.

R_(f) (silica, 100% EtOAc)=0.34. ¹ H NMR (300 MHz, CD₃ OD) δ 7.28 (m,1H), 7.10 (d, J=6.0 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H), 6.91 (t, J=6.0 Hz,1H), 3.58 (m, 1H), 2.67 (m, 4H).

3-(3-Fluoro-phenyl)-pentanedioic acid monomethyl ester (2-4)

A mixture of 3-(3-fluoro-phenyl)-pentanedioic acid (2-3) (2.86 g, 12.7mmol) and Ac₂ O (20 mL) was refluxed for 3 hr at 130° C. It wasconcentrated under diminished pressure to provide an oil which wassubsequently diluted with 15 mL CH₂ Cl₂. To the resulting solution wasadded 10 mL MeOH and DMAP (50 mg, 0.04 mmol). The mixture was stirredfor 12 hr and concentrated to afford 24 as a solid which was used in thenext step without further purification.

R_(f) (silica, 100% EtOAc)=0.73. ¹ H NMR (300 MHz, CDCl₃) δ 7.26 (m,1H), 7.01 (d, J=5.9 Hz, 1H), 6.92 (m, 2H), 3.62 (m, 4H), 2.70 (m, 4H).

2-Allyl-3-(3-fluoro-phenyl)-pentanedioic acid 1-methyl ester (2-5)

To a cooled (-78° C.) solution of LDA (7.1 mL, 2.0 M, 14.2 mmol) in 50mL THF was added a solution of 3-(3-fluoro-phenyl)-pentanedioic acidmonomethyl ester (2-4) (1.58 g, 6.58 mmol) in 10 mL THF gradually. Themixture was stirred for 40 min, treated with allyl bromide (1.71 mL,19.7 mmol) at -78° C. and stirred overnight while it was warmed to roomtemperature. It was then concentrated and diluted with 20 mL CH₂ Cl₂ and15 mL EtOH. To the resulting solution was added EDAC (1.88 g, 9.87 mmol)and DMAP (25 mg, 0.02 mmol). After stirring for 5 hr, the reaction wasquenched with 20 mL 10% NaHCO₃ and extracted with EtOAc (×3). Thecombined organic layers were washed with brine, dried (Na₂ SO₄) andconcentrated to provide 2-5 as an oil, which was further purified usingflash silica chromatography (Hexane/EtOAc, 4:1).

R_(f) (silica; EtOAc/hexane 1:2)=0.53.

3-(3-Fluoro-phenyl)-2-(2-oxo-ethyl)-pentanedioic acid 1-methyl ester(2-6A, 2-6B)

A mixture of 2-allyl-3-(3-fluoro-phenyl)-pentanedioic acid 1-methylester (2-5) (1.01 g, 3.28 mmol) and Sudan Red B (0.01 g) in 100 mL CH₂Cl₂ was treated with ozone at -78° C. for 20 min. Then excess ozone waspurged with argon, followed with the addition of PPh₃ (2.00 g, 7.63mmol). The mixture was stirred for 30 min and concentrated underdiminished pressure. The residue was purified by flash silicachromatography (EtOAc/Hexane, 1:3) to provide the desired product as twoseparated pairs of enantiomers (2-6A and 2-6B).

R_(f) (of enantiomeric pair 2-6A, silica, EtOAc/hexane 1:2)=0.26; R_(f)(of enantiomeric pair 2-6B, silica, EtOAc/hexane 1:2)=0.21.

3-(3-Fluoro-phenyl)-3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl}-propionicacid ethyl ester (2-7A)

To a mixture of3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propylamine (1-8) (67 mg,0.36 mmol) and 3-(3-fluoro-phenyl)-2-(2-oxoethyl)-pentanedioic acid1-methyl ester 2-6A (110 mg, 0.36 mmol) in 5 mL 1,2-dichloroethane wasadded anhydrous hydrogen chloride in ethyl ether (1.0 M, 0.70 ml, 0.7mmol). After 10 min, triethylamine (0.14 mL, 1.1 mmol) and 4 Å molecularsieves were added. The mixture was stirred for 3 hr. It was treated withNaBH(OAc)₃ (111 mg, 0.53 mmol) and stirred for 12 hr. The reaction wasquenched with 10% NaHCO₃ and extracted with EtOAc (×3). The combinedorganic layers were washed with brine and dried (Na₂ SO₄). After solventremoval the residue was purified by flash silica chromatography (CHCl₃/MeOH, 10:1) to provide the enantiomeric pair 2-7A as an oil.

R_(f) (silica, CHCl₃ /MeOH, 10:1)=0.3.

3-(3-Fluoro-phenyl)-3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl}-propionicacid ethyl ester (2-7B)

Following the procedure described for preparing 2-7A from 2-6A, 2-6Bfurnished the enantiomeric pair 2-7B as an oil.

R_(f) (silica, CHCl₃ /MeOH, 10:1)=0.3.

3-(3-Fluoro-phenyl)-3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl}-propionicacid (2-8A)

A mixture of 2-7A (100 mg, 0.22 mmol) and aqueous LiOH (0.6 mL, 0.6mmol) in 4 mL ethanol and 2 mL water was stirred for 24 hr. It wastreated with 3 N HCl and concentrated. The residue was purified byreverse phase HPLC (C18 column; gradient: H₂ O/CH₃ CN/TFA from 95:5:0.1to 5:95:0.1 over 45 min) to give the enantiomeric pair 2-8A as the TFAsalt.

FAB mass spectrum m/z=426.2 (m+1). ¹ H NMR (300 MHz, CD₃ OD) δ 7.59 (d,J=7.5 Hz, 1H), 7.33-7.25 (m, 1H), 7.12-7.03 (m, 2H), 6.96-6.90 (m, 1H),6.59 (d, J=7.5 Hz, 1H), 3.64-3.57 (m, 1H), 3.51 (t, J=5.7 Hz, 2H),3.27-3.12 (m, 4H), 3.08-3.00 (m, 1H), 2.93-2.71 (m, 4H), 2.56-2.45 (m,2H), 2.08-1.92 (m, 3H), 1.83-1.71 (m, 3H) Anal. Calcd. for C₂₄ H₂₈ N₃ O₃F₁ 1.75.TFA: C, 52.24; H, 4.87; N, 6.65; found: C, 52.25; H, 4.88; N,6.41

3-(3-Fluoro-phenyl)-3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl}-propionicacid (2-8B)

Following the procedure described for preparing 2-8A from 2-7A, 2-7Bfurnished the enantiomeric pair 2-8B as the TFA salt.

¹ H NMR (300 MHz, CD₃ OD) δ 7.59 (d, J=7.5 Hz, 1H), 7.33-7.26 (m, 1H),7.13-7.03 (m, 2H), 6.98-6.92 (m, 1H), 6.62 (d, J=7.5 Hz, 1H), 3.60-3.49(m, 4H), 3.28-3.22 (m, 2H), 3.02-2.89 (m, 4H), 2.87-2.81 (m, 2H), 2.58(t, J=7.2 Hz, 2H), 2.20-2.07 (m, 1H), 2.00-1.76 (m, 5H). Anal. Calcd.for C₂₄ H₂₈ N₃ O₃ F₁ 1.60.TFA: C, 53.58; H, 4.93; N, 6.89 found: C,53.81; H, 4.81; N, 6.84 ##STR14##

3-(Quinolin-3-yl)-acrylic acid tert-butyl ester (3-2)

A mixture of 3-bromoquinoline 3-1(25 g, 120 mmol), acrylic acidtert-butyl ester (100 mL, 672 mmol), triethylamine (50 mL, 300 mmol) andPd(OAc)₂ (1.61 g, 7.2 mmol) in acetonitrile (100 mL) was refluxed for 18hr. It is then cooled, diluted with 500 mL CH₂ Cl₂ and filtered. Thesolution was washed with 10% NaHCO₃, dried and concentrated. The residuewas dissolved in 50 ml hot CH₂ Cl₂ and diluted with 300 mL hexane. Afterstanding, the desired product 3-2 was obtained as a crystallinecompound.

R_(f) (silica, EtOAc/hexane 1:2)=0.49. ¹ H NMR (300 MHz, CDCl₃) δ 9.08(d, J=1.8 Hz, 1H), 8.22 (d, J=1.8 Hz, 1H), 8.11 (d, J=8.4, 1H), 7.85 (d,J=7.8 Hz, 1H), 7.77-7.71 (m, 2H), 7.58 (t, J=7.2 Hz, 1H). 6.60 (d,J=16.2 Hz, 1H), 1.57 (s, 9H).

2-Ethoxycarbonyl-3-(quinolin-3-yl)-pentanedioic acid 5-tert-butyl ester1-ethyl ester (3-3)

Following the procedure described for preparing 2-2 from 2-1, 3-2furnished 3-3 as an oil.

R_(f) (silica, EtOAc/hexane 1:2)=0.28.

3-(Quinolin-3-yl)-pentanedioic acid (3-4)

Following the procedure described for preparing 2-3 from 2-2, 3-3furnished 3-4 as a solid.

R_(f) (silica, EtOAc/MeOH 5:1)=0.1. ¹ H NMR (300 MHz, CD₃ OD) δ 9.31 (d,J=1.8 Hz, 1H), 9.22 (d, J=1.8 Hz, 1H), 8.32 (d, J=8.1, 1H), 8.23 (d,J=8.7 Hz, 1H), 8.18-8.12 (m, 1H), 8.00-7.95 (m, 1H). 3.99-3.89 (m, 1H),3.06-2.90 (m, 4H).

3-(Quinolin-3-yl)-pentanedioic acid dimethyl ester (3-5)

A mixture of 3-quinolin-3-yl-pentanedioic acid 3-4 (1.00 g, 3.86 mmol)and 2 mL conc. H₂ SO₄ in 20 mL methanol was refluxed for 12 hr. Aftersolvent removal, the residue was diluted with 100 mL ice-water, treatedwith 10% Na₂ CO₃ and extracted with EtOAc (×3). The combined organiclayers were washed with brine, dried (Na₂ SO₄) and concentrated toafford 3-5 as a solid.

R_(f) (silica, EtOAc)=0.63. ¹ H NMR (300 MHz, CDCl₃) δ 8.84 (d, J=2.1Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.00 (d, J=1.8, 1H), 7.79 (d, J=7.8 Hz,1H), 7.72-7.66 (m, 1H), 7.57-7.51 (m, 1H). 3.94-3.84 (m, 1H), 2.92-2.75(m, 4H).

2-Allyl-3-(quinolin-3-yl)-pentanedioic acid dimethyl ester (3-6)

Following the procedure described for preparing 2-5,3-(quinolin-3-yl)-pentanedioic acid dimethyl ester 3-4 furnished 3-6 asa solid.

R_(f) (silica, CHCl₃ /MeOH 10:1)=0.64.

2-(2-Oxo-ethyl)-3-(quinolin-3-yl)-pentanedioic acid dimethyl ester(3-7A, 3-7B)

Following the procedure described for preparing 2-6A and 2-6B from 2-5,3-6 furnished two separated pairs of enantiomers 3-7A and 3-7B.

R_(f) (of enantiomeric pair 3-7A, silica, CHCl₃ /MeOH 10:1)=0.44; R_(f)(of enantiomeric pair 3-7B, silica, CHCl₃ /MeOH 10:1)=0.40.

3-{2-Oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]pyrrolidin-3-yl}-3-(quinolin-3-yl)-propionicacid methyl ester (3-8A-A, 3-8A-B)

Following the procedure described for preparing 2-7A from 2-6A, 3-7Afurnished the enantiomeric pair 3-8A as an oil.

TLC R_(f) (silica, CHCl₃ /MeOH 10:1)=0.33.

The two enantiomers were separated using HPLC (Chiralcel OJ; gradient:hexane/ethanol/DEA from 60:40:0.1 to 20:80:0.1 over 45 min) to give thefast-moving enantiomer 3-8A-A and the slow-moving enantiomer 3-8A-B.

3-{2-Oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl}-3-(quinolin-3-yl)-propionicacid methyl ester (3-8B-A, 3-8B-B)

Following the procedure described for preparing 2-7A from 2-6A, 3-7Bfurnished the enantiomeric pair 3-8B as an oil.

TLC R_(f) (silica, CHCl₃ /MeOH 10:1)=0.33.

The two enantiomers were separated using HPLC (Chiralcel OJ; gradient:hexane/ethanol/DEA from 65:35:0.1 to 0:100:0.1 over 60 min) to affordthe fast-moving enantiomer 3-8B-A and the slow-moving enantiomer 3-8B-B.

3-{2-Oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl}-3-(quinolin-3-yl)-propionicacid (3-9A-A)

Following the procedure described for preparing 2-8A from 2-7A, 3-8A-Afurnished the single enantiomer 3-9A-A which was purified by reversephase HPLC (C18 column; gradient: H₂ O/CH₃ CN/TFA from 95:5:0.1 to5:95:0.1 over 45 min) to provide pure 3-9A-A as a TFA salt.

¹ H NMR (300 MHz, CD₃ OD) δ 9.15 (d, J=2.1 Hz, 1H), 8.94 (s, 1H), 8.17(d, J=8.1 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.99-7.93 (m, 1H), 7.84-7.79(m, 1H), 7.51 (d, J=7.5 Hz, 1H), 6.46 (d, J=7.2 Hz, 1H), 4.03-3.96 (m,1H), 3.50 (t, J=6.0 Hz, 2H), 3.40-3.01 (m, 7H), 2.81 (t, J=6.3 Hz, 2H),2.40-1.62 (m, 8H) Anal. Calcd. for C₂₇ H₃₀ N₄ O₃ 2.45.TFA: C, 51.92; H,4.43; N, 7.59; found: C, 51.97; H, 4.12; N, 7.41.

3-{2-Oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl-}-3-(quinolin-3-yl)-propionicacid (3-9A-B)

Following the procedure described for preparing 2-8A, 3-8A-B furnishedthe single enantiomer 3-9A-B, which was purified by reverse phase HPLC(C18 column; gradient: H₂ O/CH₃ CN/TFA from 95:5:0.1 to 5:95:0.1 over 45min) to give pure 3-9A-B as a TFA salt.

¹ H NMR (300 MHz, CD₃ OD) δ 9.15 (d, J=2.1 Hz, 1H), 8.94 (s, 1H), 8.17(d, J=8.1 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.99-7.93 (m, 1H), 7.84-7.79(m, 1H), 7.51 (d, J=7.5 Hz, 1H), 6.46 (d, J=7.2 Hz, 1H), 4.03-3.96 (m,1H), 3.50 (t, J=6.0 Hz, 2H), 3.40-3.01 (m, 7H), 2.81 (t, J=6.3 Hz, 2H),2.40-1.62 (m, 8H) Anal. Calcd for C₂₇ H₃₀ N₄ O₃ 2.5.TFA: C, 51.50; H,4.43; N, 7.51; found: C, 51.49; H, 4.24; N, 7.26.

3-{2-Oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl}-3-(quinolin-3-yl)-propionicacid (3-9B-A)

Following the procedure described for preparing 2-8A, 3-8B-A furnishedthe single enantiomer 3-9B-A, which was purified by reverse phase HPLC(C18 column; gradient: H₂ O/CH₃ CN/TFA from 95:5:0.1 to 5:95:0.1 over 45min) to give pure 3-9B-A as a TFA salt.

¹ H NMR (300 MHz, CD₃ OD) δ 9.19 (d, J=2.1 Hz, 1H), 8.99 (d, J=1.5 Hz,1H), 8.19 (t, J=8.4 Hz, 2H), 8.08-8.02 (m, 1H), 7.89-7.83 (m, 1H), 7.54(d, J=7.2 Hz, 1H), 6.55 (d, J=7.2 Hz, 1H), 3.80-3.72 (m, 1H), 3.48 (t,J=5.4 Hz, 2H), 3.40-3.01 (m, 7H), 2.81 (t, J=6.6 Hz, 2H), 2.57-2.30 (m,3H), 2.08-1.73 (m, 5H). Anal. Calcd for C₂₇ H₃₀ N₄ O₃ 2.5.TFA: C, 48.84;H, 4.78; N, 7.12; found: C, 48.85; H, 4.02; N, 6.85.

3-{2-Oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl}-3-(quinolin-3-yl)-propionicacid (3-9B-B)

Following the procedure described for preparing 2-8A, 3-8B-B furnishedthe single enantiomer 3-9B-B which was purified by reverse phase HPLC(C18 column; gradient: H₂ O/CH₃ CN/TFA from 95:5:0.1 to 5:95:0.1 over 45min) to give pure 3-9B-B as a TFA salt.

¹ H NMR (300 MHz, CD₃ OD) δ 9.19 (d, J=2.1 Hz, 1H), 8.99 (d, J=1.5 Hz,1H), 8.19 (t, J=8.4 Hz, 2H), 8.08-8.02 (m, 1H), 7.89-7.83 (m, 1H), 7.54(d, J=7.2 Hz, 1H), 6.55 (d, J=7.2 Hz, 1H), 3.80-3.72 (m, 1H), 3.48 (t,J=5.4 Hz, 2H), 3.40-3.01 (m, 7H), 2.81 (t, J=6.6 Hz, 2H), 2.57-2.30 (m,3H), 2.08-1.73 (m, 5H). Anal. Calcd for C₂₇ H₃₀ N₄ O₃ 2.5.TFA: C, 49.64;H, 4.67; N, 7.24; found: C, 49.64; H, 3.99; N, 7.00. ##STR15##

N-(4-Iodo-phenylsulfonylamino)-L-asparagine (A-2)

To a stirred solution of acid A-1 (4.39 g, 33.2 mmol), NaOH (1.49 g,37.2 mmol), dioxane (30 ml) and H₂ O (30 ml) at 0° C. was added pipsylchloride (10.34 g, 34.2 mmol). After ˜5 minutes, NaOH (1.49, 37.2 mmol),dissolved in 15 ml H₂ O, was added followed by the removal of thecooling bath. After 2.0 h, the reaction mixture was concentrated. Theresidue was dissolved in H₂ O (300 ml) and then washed with EtOAc. Theaqueous portion was cooled to 0° C. and then acidified with concentratedHCl. The solid was collected and then washed with Et₂ O to provide acidA-2 as a white solid.

¹ H NMR (300 MHz, D₂ O) δ 7.86 (d, 2H, J=8 Hz), 7.48 (d, 2H, J=8 Hz)3.70 (m, 1H), 2.39 (m, 2H).

2(S)-(4-Iodo-phenylsulfonylamino)-β-alanine (A-3)

To a stirred solution of NaOH (7.14 g, 181.8 mmol) and H₂ O (40 ml) at0° C. was added Br₂ (1.30 ml, 24.9 mmol) dropwise over a ten minuteperiod. After ˜5 minutes, acid A-2 (9.9 g, 24.9 mmol), NaOH (2.00 g,49.8 mmol) and H₂ O (35 ml) were combined, cooled to 0° C. and thenadded in a single portion to the reaction. After stirring for 20 minutesat 0° C., the reaction was heated to 90° C. for 30 minutes and thenrecooled to 0° C. The pH was adjusted to ˜7 by dropwise addition ofconcentrated HCl. The solid was collected, washed with EtOAc, and thendried in vacuo to provide acid A-3 as a white solid.

¹ H NMR (300 MHz, D₂ O) δ 8.02 (d, 2H, J=8 Hz), 7.63 (d, 2H, J=8 Hz),4.36 (m, 1H), 3.51 (dd, 1H, J=5 Hz, 13 Hz) 3.21 (m, 1H).

Ethyl 2(S)-(4-iodo-phenylsulfonylamino)-β-alanine-hydrochloride (A-4)

HCl gas was rapidly bubbled through a suspension of acid A-3 (4.0 g,10.81 mmol) in EtOH (50 ml) at 0° C. for 10 minutes. The cooling bathwas removed and the reaction was heated to 60° C. After 18 h, thereaction was concentrated to provide ester A-4 as a white solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.98 (d, 2H, J=8 Hz), 7.63 (d, 2H, J=8 Hz),4.25 (q, 1H, J=5 Hz), 3.92 (m, 2H), 3.33 (m, 1H), 3.06 (m, 1H), 1.01 (t,3H, J=7 Hz).

Ethyl 4-[2-(2-Aminopyridin-6-yl)ethyl]benzoate (A-5a)

A mixture of ester A-5 (700 mg, 2.63 mmol), (for preparation, see:Scheme 29 of PCT International Application Publication No. WO 95/32710,published Dec. 7, 1995) 10% Pd/C (350 mg) and EtOH were stirred under 1atm H₂. After 20 h, the reaction was filtered through a celite pad andthen concentrated to provide ester A-5a as a brown oil.

TLC R_(f) =0.23 (silica, 40% EtOAc/hexanes) ¹ H NMR (300 MHz, CDCl₃) δ7.95 (d, 2H, J=8 Hz), 7.26 (m, 3H), 6.43 (d, 1H, J=7 Hz), 6.35 (d, 1H,J=8 Hz), 4.37 (m, 4H), 3.05 (m, 2H), 2.91 (m, 2H), 1.39 (t, 3H, J=7 Hz).

4-[2-(2-Aminopyridin-6-yl)ethyl]benzoic acid hydrochloride (A-6)

A suspension of ester A-5a (625 mg, 2.31 mmol) in 6 N HCl (12 ml) washeated to 60° C. After ˜20 h, the reaction was concentrated to give acidA-6 as a tan solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.96 (d, 2H, J=8 Hz), 7.80 (m, 1H), 7.33 (d,2H, J=8 Hz), 6.84 (d, 1H, J=9 Hz), 6.69 (d, 1H, J=7 Hz), 3.09 (m, 4H).

Ethyl4-[2-(2-Aminopyidin-6-yl)ethyl]benzoyl-2(S)-(4-iodo-phenylsulfonylamino)-.beta.-alanine(A-7)

A solution of acid 15-6 (400 mg, 1.43 mmol), amine A-4 (686 mg, 1.57mmol), EDC (358 mg, 1.86 mmol), HOBT (252 mg, 1.86 mmol), NMM (632 μl,5.72 mmol) in DMF (10 ml) was stirred for ˜20 h. The reaction wasdiluted with EtOAc and then washed d with sat. NaHCO₃, brine, dried(MgSO₄) and concentrated. Flash chromatography (silica, EtOAc then 5%isopropanol/EtOAc) provided amide A-7 as a white solid.

TLC R_(f) =0.4 (silica, 10% isopropanol/EtOAc) ¹ H NMR (300 MHz, CD₃ OD)δ 7.79 (d, 2H, J=9 Hz) 7.61 (d, 2H, J=8 Hz), 7.52 (d, 2H, J=9 Hz), 7.29(m, 1H), 7.27 (d, 2H, J=8 Hz), 4.20 (m, 1H), 3.95 (q, 2H, J=7 Hz), 3.66(dd, 1H, J=6 Hz, 14 Hz), 3.49 (dd, 1H, J=8 Hz, 13 Hz), 3.01 (m, 2H),2.86 (m, 2H), 1.08 (t, 3H, J=7 Hz).

4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-(4-iodophenyl-sulfonylamino)-.beta.-alanine(A-8)

A solution of ester A-7 (200 mg, 0.3213 mmol) and 6N HCl (30 ml) washeated to 60° C. After ˜20 h, the reaction mixture was concentrated.Flash chromatography (silica, 20:20:1:1 EtOAc/EtOH/NH₄ OH/H₂ O) providedacid A-8 as a white solid.

TLC R_(f) =0.45 (silica, 20:20:1:1 EtOAc/EtOH/NH₄ OH/H₂ O) ¹ H NMR (400MHz, DMSO) δ 8.40 (m, 1H), 8.14 (Bs, 1H), 7 .81 (d, 2H, J=8 Hz), 7.62(d, 2H, J=8 Hz), 7.48 (d, 2H, J=8 Hz), 7.27 (m, 3H), 6.34 (d, 1H, J=7Hz), 6.25 (d, 1H, J=8 Hz), 5.85 (bs, 2H), 3.89 (bs, 1H), 3.35 (m, 2H),2.97 (m, 2H), 2.79 (m, 2H).

4-[2-(2-Aminopyridin-6-yl)ethyl)benzoyl-2(S)-(4-trimethylstannyl-phenylsulfonylamino-β-alanine(A-9)

A solution of iodide A-8 (70 mg, 0.1178 mmol), [(CH₃)₃ Sn]₂ (49 μl,0.2356 mmol), Pd(PPh₃)₄ (5 mg) and dioxane (7 ml) was heated to 90° C.After 2 h, the reaction was concentrated and then purified bypreparative HPLC (Delta-Pak C₁₈ 15 μM 100A°, 40×100 mm; 95:5 then 5:95H₂ O/CH₃ CN) to provide the trifluoroacetate salt. The salt wassuspended in H₂ O (10 ml), treated with NH₄ OH (5 drops) and thenlyophilized to provide amide A-9 as a white solid.

¹ H NMR (400 MHz, DMSO) δ 8.40 (m, 1H), 8.18 (d, 1H, J=8 Hz), 7.67 (m,5H), 7.56 (d, 2H, J=8 Hz), 7.29 (d, 2H, J=8 Hz), 6.95-7.52 (m, 2H), 6.45(bs, 2H), 4.00 (m, 1H), 3.50 (m, 1H), 3.33 (m, 1H), 2.97 (m, 2H), 2.86(m, 2H).

4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-4-¹²⁵iodophenylsulfonylamino-β-alanine (A-10)

An iodobead (Pierce) was added to a shipping vial of 5 mCi of Na¹²⁵ I(Amersham, IMS30) and stirred for five minutes at room temperature. Asolution of 0.1 mg of A-9 in 0.05 mL of 10% H₂ SO₄ /MeOH was made andimmediately added to the Na¹²⁵ I/iodobead vial. After stirring for threeminutes at room temperature, approximately 0.04-0.05 mL of NH₄ OH wasadded so the reaction mixture was at pH 6-7. The entire reaction mixturewas injected onto the HPLC for purification [Vydac peptide-protein C-18column, 4.6×250 mm, linear gradient of 10% acetonitrile (0.1% (TFA):H₂ O(0.1% TFA) to 90% acetonitrile (0.1% TFA):H₂ O (0.1% TFA) over 30minutes, 1 mL/min]. The retention time of A-10 is 17 minutes under theseconditions. Fractions containing the majority of the radioactivity werepooled, lyophilized and diluted with ethanol to give approximately 1 mCiof A-10, which coeluted on HPLC analysis with an authentic sample ofA-8.

Instrumentation: Analytical and preparative HPLC was carried out using aWaters 600E Powerline Multi Solvent Delivery System with 0.1 mL headswith a Rheodyne 7125 injector and a Waters 990 Photodiode Array Detectorwith a Gilson FC203 Microfraction collector. For analytical andpreparative HPLC, a Vydac peptide-protein C-18 column, 4.6×250 mm wasused with a C-18 Brownlee modular guard column. The acetonitrile usedfor the HPLC analyses was Fisher Optima grade. The HPLC radiodetectorused was a Beckman 170 Radioisotope detector. A Vydac C-18 protein andpeptide column, 3.9×250 mm was used for analytical and preparative HPLC.Solutions of radioactivity were concentrated using a Speedvac vacuumcentrifuge. Calibration curves and chemical concentrations weredetermined using a Hewlett Packard Model 8452A UV/Vis Diode ArraySpectrophotometer. Sample radioactivities were determined in a PackardA5530 gamma counter.

The test procedures employed to measure ανβ3 and ανβ5 binding and thebone resorption inhibiting activity of the compounds of the presentinvention are described below.

BONE RESORPTION-PIT ASSAY

When osteoclasts engage in bone resorption, they can cause the formationof pits in the surface of bone that they are acting upon.

Therefore, when testing compounds for their ability to inhibitosteoclasts, it is useful to measure the ability of osteoclasts toexcavate these resorption pits when the inhibiting compound is present.

Consecutive 200 micron thick cross sections from a 6 mm cylinder ofbovine femur diaphysis are cut with a low speed diamond saw (Isomet,Beuler, Ltd., Lake Bluff, Ill.). Bone slices are pooled, placed in a 10%ethanol solution and refrigerated until further use.

Prior to experimentation, bovine bone slices are ultrasonicated twice,20 minutes each in H₂ O. Cleaned slices are placed in 96 well platessuch that two control lanes and one lane for each drug dosage areavailable. Each lane represents either triplicate or quadruplicatecultures. The bone slices in 96 well plates are sterilized by UVirradiation. Prior to incubation with osteoclasts, the bone slices arehydrated by the addition of 0.1 ml αMEM, pH 6.9 containing 5% fetalbovine serum and 1% penicillin/streptomycin.

Long bones from 7-14 day old rabbits (New Zealand White Hare) aredissected, cleaned of soft tissue and placed in αMEM containing 20 mMHEPES. The bones are minced using scissors until the pieces are <1 mmand transferred to a 50 ml tube in a volume of 25 ml. The tube is rockedgently by hand for 60 cycles, the tissue is sedimented for 1 min., andthe supernatant is removed. Another 25 ml of medium is added to thetissue and rocked again. The second supernatant is combined with thefirst. The number of cells is counted excluding erythrocytes (typically˜2×10⁷ cells/ml). A cell suspension consisting of 5×10⁶ /ml in αMEMcontaining 5% fetal bovine serum, 10 nM 1,25(OH)₂ D₃, andpencillin-streptomycin is prepared. 200 ml aliquots are added to bovinebone slices (200 mm×6 mm) and incubated for 2 hrs. at 37° C. in ahumidified 5% CO₂ atmosphere. The medium is removed gently with amicropipettor and fresh medium containing test compounds is added. Thecultures are incubated for 48 hrs., and assayed for c-telopeptide(fragments of the a1 chain of type I collagen) by Crosslaps for culturemedia (Herlev, Denmark).

Bovine bone slices are exposed to osteoclasts for 20-24 hrs and areprocessed for staining. Tissue culture media is removed from each boneslice. Each well is washed with 200 ml of H₂ O, and the bone slices arethen fixed for 20 minutes in 2.5% glutaraldehyde, 0.1 M cacodylate, pH7.4. After fixation, any remaining cellular debris is removed by 2 min.ultrasonication in the presence of 0.25 M NH₄ OH followed by 2×15 minultrasonication in H₂ O. The bone slices are immediately stained for 6-8min with filtered 1% toluidine blue and 1% borax.

After the bone slices have dried, resorption pits are counted in testand control slices. Resorption pits are viewed in a Microphot Fx (Nikon)fluorescence microscope using a polarizing Nikon IGS filter cube. Testdosage results are compared with controls and resulting IC₅₀ values aredetermined for each compound tested.

The appropriateness of extrapolating data from this assay to mammalian(including human) disease states is supported by the teaching found inSato, M., et al., Journal of Bone and Mineral Research, Vol. 5, No. 1,pp.31-40, 1990, which is incorporated by reference herein in itsentirety. This article teaches that certain bisphosphonates have beenused clinically and appear to be effective in the treatment of Paget'sdisease, hypercalcemia of malignancy, osteolytic lesions produced bybone metastases, and bone loss due to immobilization or sex hormonedeficiency. These same bisphosphonates are then tested in the resorptionpit assay described above to confirm a correlation between their knownutility and positive performance in the assay.

EIB ASSAY

Duong et al., J. Bone Miner. Res., 8: S378 (1993) describes a system forexpressing the human integrin ανβ3. It has been suggested that theintegrin stimulates attachment of osteoclasts to bone matrix, sinceantibodies against the integrin, or RGD-containing molecules, such asechistatin (European Publication 382 451), can effectively block boneresorption.

Reaction Mixture:

1. 175 μl TBS buffer (50 mM Tris•HCl pH 7.2, 150 mM NaCl, 1% BSA, 1 mMCaCl₂, 1 mM MgCl₂).

2. 25 μl cell extract (dilute with 100 mM octylglucoside buffer to give2000 cpm/25 μl).

3. ¹²⁵ I-echistatin (25 μl/50,000 cpm) (see EP 382 451).

4. 25 μl buffer (total binding) or unlabeled echistatin (non-specificbinding).

The reaction mixture was then incubated for 1 h at room temp. Theunbound and the bound ανβ3 were separated by filtration using a SkatronCell Harvester. The filters (prewet in 1.5% polyethyleneimine for 10mins) were then washed with the wash buffer (50 mM Tris HCl, 1 mM CaCl₂/MgCl₂, pH 7.2). The filter was then counted in a gamma counter.

SPA ASSAY

MATERIALS:

1. Wheat germ agglutinin Scintillation Proximity Beads (SPA): Amersham

2. Octylglucopyranoside: Calbiochem

3. HEPES: Calbiochem

4. NaCl: Fisher

5. CaCl₂ : Fisher

6. MgCl₂ : SIGMA

7. Phenylmethylsulfonylfluoride (PMSF): SIGMA

8. Optiplate: PACKARD

9. Compound A-10 (specific activity 500-1000 Ci/mmole)

10. test compound

11. Purified integrin receptor: α.sub.ν β3 was purified from 293 cellsoverexpressing α.sub.ν β3 (Duong et al., J. Bone Min. Res., 8:S378,1993) according to Pytela (Methods in Enzymology, 144:475, 1987)

12. Binding buffer: 50 mM HEPES, pH 7.8, 100 mM NaCl, 1 mM Ca^(2+/)Mg²⁺, 0.5 mM PMSF

13. 50 mM octylglucoside in binding buffer: 50-OG buffer

PROCEDURE:

1. Pretreatment of SPA Beads:

500 mg of lyophilized SPA beads were first washed four times with 200 mlof 50-OG buffer and once with 100 ml of binding buffer, and thenresuspended in 12.5 ml of binding buffer.

2. Preparation of SPA Beads and Receptor Mixture

In each assay tube, 2.5 μl (40 mg/ml) of pretreated beads were suspendedin 97.5 μl of binding buffer and 20 μl of 50-OG buffer. 5 μl (˜30 ng/μl)of purified receptor was added to the beads in suspension with stirringat room temperature for 30 minutes. The mixture was then centrifuged at2,500 rpm in a Beckman GPR Benchtop centrifuge for 10 minutes at 4° C.The pellets were then resuspended in 50 μl of binding buffer and 25 μlof 50-OG buffer.

3. Reaction

The following were sequentially added into Optiplate in correspondingwells:

(i) Receptor/beads mixture (75 ml)

(ii) 25 μl of each of the following: compound to be tested, bindingbuffer for total binding or A-8 for non-specific binding (finalconcentration 1 μM)

(iii) A-10 in binding buffer (25 μl, final concentration 40 pM)

(iv) Binding buffer (125 μl)

(v) Each plate was sealed with plate sealer from PACKARD and incubatedovernight with rocking at 4° C.

4. Plates were counted using PACKARD TOPCOUNT

5. % inhibition was calculated as follows:

A=total counts

B=nonspecific counts

C=sample counts

% inhibition=[{(A-B)-(C-B)}/(A-B)]/(A-B)×100

OCFORM ASSAY

Osteoblast-like cells (1.8 cells), originally derived from mousecalvaria, were plated in CORNING 24 well tissue culture plates in αMEMmedium containing ribo- and deoxyribonucleosides, 10% fetal bovine serumand penicillin-streptomycin. Cells were seeded at 40,000/well in themorning. In the afternoon, bone marrow cells were prepared from six weekold male Balb/C mice as follows:

Mice were sacrificed, tibiae removed and placed in the above medium. Theends were cut off and the marrow was flushed out of the cavity into atube with a 1 mL syringe with a 27.5 gauge needle. The marrow wassuspended by pipetting up and down. The suspension was passedthrough >100 μm nylon cell strainer. The resulting suspension wascentrifuged at 350×g for seven minutes. The pellet was resuspended, anda sample was diluted in 2% acetic acid to lyse the red cells. Theremaining cells were counted in a hemacytometer. The cells were pelletedand resuspended at 1×10⁶ cells/mL. 50 μL was added to each well of 1.8cells to yield 50,000 cells/well and 1,25-dihydroxy-vitamin D₃ (D₃) wasadded to each well to a final concentration of 10 nM. The cultures wereincubated at 37° C. in a humidified, 5% CO₂ atmosphere. After 48 h, themedium was changed. 72 h after the addition of bone marrow, testcompounds were added with fresh medium containing D₃ to quadruplicatewells. Compounds were added again after 48 h with fresh mediumcontaining D₃. After an additional 48 h., the medium was removed, cellswere fixed with 10% formaldehyde in phosphate-buffered saline for 10minutes at room temperature, followed by a 1-2 minute treatment withethanol:acetone (1:1) and air dried. The cells were then stained fortartrate resistant acid phosphatase as follows:

The cells were stained for 10-15 minutes at room temperature with 50 mMacetate buffer, pH 5.0 containing 30 mM sodium tartrate, 0.3 mg/mL FastRed Violet LB Salt and 0.1 mg/mL Naphthol AS-Mx phosphate. Afterstaining, the plates were washed extensively with deionized water andair dried. The number of multinucleated, positive staining cells wascounted in each well.

ανβ5 ATTACHMENT ASSAY

Duong et al., J. Bone Miner. Res., 11: S290 (1996), describes a systemfor expressing the human ανβ5 integrin receptor.

Materials:

1. Media and solutions used in this assay are purchased from BRL/Gibco,except BSA and the chemicals are from Sigma.

2. Attachment medium: HBSS with 1 mg/ml heat-inactivated fatty acid freeBSA and 2 mM CaCl₂.

3. Glucosaminidase substrate solution: 3.75 mM p-nitrophenylN-acetyl-beta-D-glucosaminide, 0.1 M sodium citrate, 0.25% Triton, pH5.0.

4. Glycine-EDTA developing solution: 50 mM glycine, 5 mM EDTA, pH 10.5.

Methods:

1. Plates (96 well, Nunc Maxi Sorp) were coated overnight at 4° C. withhuman vitronectin (3 ug/ml) in 50 mM carbonate buffer (pH 9/0.6), using100 μ/well. Plates were then washed 2× with DPBS and blocked with 2% BSAin DPBS for 2 h at room temperature. After additional washes (2×) withDPBS, plates were used for cell attachment assay.

2. 293 (ανβ5) cells were grown in MEM media in presence of 10% fetalcalf serum to 90% confluence. Cells were then lifted from dishes with1×Trypsin/EDTA and washed 3× with serum free MEM. Cells were resuspendedin attachment medium (3×10⁵ cells/ml).

3. Test compounds were prepared as a series of dilutions at 2×concentrations and added as 50 μl/well. Cell suspension was then addedas 50 μl/well. Plates were incubated at 37° C. with 55 CO₂ for 1 hour toallow attachment.

4. Non-adherent cells were removed by gently washing the plates (3×)with DPBS and then incubated with glucosaminidase substrate solution(100 μl/well), overnight at room temperature in the dark. To quantitatecell numbers, standard curve of glucosaminidase activity was determinedfor each experiment by adding samples of cell suspension directly towells containing the enzyme substrate solution.

5. The next day, the reaction was developed by addition of 185 μl/wellof glycine/EDTA solution and reading absorbance at 405 nm using aMolecular Devices V-Max plate reader.

Average test absorbance values (4 wells per test samples) werecalculated. Then, the number of attached cells at each drugconcentration was quantitated versus the standard curve of cells usingthe Softmax program.

EXAMPLE OF A PHARMACEUTICAL FORMULATION

As a specific embodiment of an oral composition, 100 mg of a compound ofthe present invention are formulated with sufficient finely dividedlactose to provide a total amount of 580 to 590 mg to fill a size O hardgel capsule.

Representative compounds of the present invention were tested and foundto bind to human ανβ3 integrin. These compounds are generally found tohave IC₅₀ values less than about 100 nM in the SPA assay.

Representative compounds of the present invention were tested andgenerally found to inhibit ≧50% the attachment of ανβ5 expressing cellsto plates coated with vitronectin at concentrations of about 1 μM.

While the invention has been described and illustrated in reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferred dosesas set forth hereinabove may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forseverity of bone disorders caused by resorption, or for otherindications for the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be limited only by the scopeof the claims which follow and that such claims be interpreted asbroadly as is reasonable.

What is claimed is:
 1. A compound having a structural formula selectedfrom the group consisting of ##STR16## wherein the dotted line arepresents a single or a double bond, provided that when a represents adouble bond, the double bond carbon atoms are substituted only with R¹⁰and R¹² ;X is selected from the group consisting of ##STR17## a 5- or6-membered monocyclic aromatic or nonaromatic ring system having 1, 2, 3or 4 heteroatoms selected from the group consisting of N, O, and Swherein the ring nitrogen atoms are unsubstituted or substituted withone R¹ substituent and the ring carbon atoms are unsubstituted orsubstituted with one or two R¹ substituents, anda 9- to 14-memberedpolycyclic ring system, wherein one or more of the rings is aromatic,and wherein the polycyclic ring system has 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O, and S wherein the ringnitrogen atoms are unsubstituted or substituted with one R¹ substituentand the ring carbon atoms are unsubstituted or substituted with one ortwo R¹ substituents; Y is selected from the group consistingof--(CH₂)_(m) --, --(CH₂)_(m) --O--(CH₂)_(n) --, --(CH₂)_(m) --NR⁴--(CH₂)_(n) --, --(CH₂)_(m) --S--(CH₂)_(n) --, --(CH₂)_(m)--SO--(CH₂)_(n) --, --(CH₂)_(m) --SO₂ --(CH₂)_(n) --, --(CH₂)_(m)--O--(CH₂)_(n) --O--(CH₂)_(p) --, --(CH₂)_(m) --O--(CH₂)_(n) --NR⁴--(CH₂)_(p) --, --(CH₂)_(m) --NR⁴ --(CH₂)_(n) --NR⁴ --(CH₂)_(p) --,--(CH₂)_(m) --O--(CH₂)_(n) --S--(CH₂)_(p) --, --(CH₂)_(m) --S--(CH₂)_(n)--S--(CH₂)_(p) --, --(CH₂)_(m) --NR⁴ --(CH₂)_(n) --S--(CH₂)_(p) --,--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --O--(CH₂)_(p) --, --(CH₂)_(m)--S--(CH₂)_(n) --O--(CH₂)_(p) --, --(CH₂)_(m) --S--(CH₂)_(n) --NR⁴--(CH₂)_(p) --, and --(CH₂)_(m) --Z--(CH₂)_(n) --, wherein Z is a 3- to10-membered monocyclic or polycyclic aromatic or nonaromatic ring systemhaving 0, 1, 2, 3, or 4 heteroatoms selected from the group consistingof N, O, and S wherein the ring nitrogen atoms are unsubstituted orsubstituted with one R¹ substituent and the ring carbon atoms areunsubstituted or substituted with one or two R¹ substituents, andwherein any methylene (CH₂) carbon atom in Y, other than in R⁴, isunsubstituted or substituted by one or two R³ substituents; and whereinR¹ and R² are each independently selected from the group consistingofhydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkyl C₁₋₆alkyl, aryl, aryl C₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃ acylamino,C₁₋₃ acylamino C₁₋₈ alkyl, (C₁₋₆ alkyl)_(p) amino, (C₁₋₆ alkyl)_(p)amino C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl,hydroxycarbonyl C₁₋₆ alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkoxycarbonylC₁₋₆ alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl,C₁₋₆ alkyloxy-C₁₋₆ alkyl, nitro, cyano, trifluoromethyl,trifluoromethoxy, trifluoroethoxy, C₁₋₈ alkyl-S(O)_(p), (C₁₋₈ alkyl)_(p)aminocarbonyl, C₁₋₈ alkyloxycarbonylamino, (C₁₋₈ alkyl)_(p)aminocarbonyloxy, (aryl C₁₋₈ alkyl)_(p) amino, (aryl)_(p) amino, arylC₁₋₈ alkylsulfonylamino, and C₁₋₈ alkylsulfonylamino; or two R¹substituents, when on the same carbon atom, are taken together with thecarbon atom to which they are attached to form a carbonyl group; each R³is independently selected from the group consisting ofhydrogen, aryl,C₁₋₁₀ alkyl, aryl-(CH₂)_(r) --O--(CH₂)_(s) --, aryl-(CH₂)_(r) S(O)_(p)--(CH₂)_(s) --, aryl-(CH₂)_(r) --C(O)--(CH₂)_(s) --, aryl-(CH₂)_(r)--C(O)--N(R⁴)-(CH₂)_(s) --, aryl-(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --,aryl-(CH₂)_(r) --N(R⁴)-(CH₂)_(s) --, halogen, hydroxyl, oxo,trifluoromethyl, C₁₋₈ alkylcarbonylamino, aryl C₁₋₅ alkoxy, C₁₋₅alkoxycarbonyl, (C₁₋₈ alkyl)_(p) aminocarbonyl, C₁₋₆ alkylcarbonyloxy,C₃₋₈ cycloalkyl, (C₁₋₆ alkyl)_(p) amino, amino C₁₋₆ alkyl,arylaminocarbonyl, aryl C₁₋₅ alkylaminocarbonyl, aminocarbonyl,aminocarbonyl C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl,HC.tbd.C--(CH₂)_(t) --, C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --, C₃₋₇cycloalkyl-C.tbd.C--(CH₂)_(t) --, aryl-C.tbd.C--(CH₂)_(t) --, C₁₋₆alkylaryl-C.tbd.C--(CH₂)_(t) --, CH₂ ═CH--(CH₂)_(t) --, C₁₋₆alkyl-CH═CH--(CH₂)_(t) --, C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,aryl-CH═CH--(CH₂)_(t) --, C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --, C₁₋₆alkyl-SO₂ --(CH₂)_(t) --, C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --, C₁₋₆alkoxy, aryl C₁₋₆ alkoxy, aryl C₁₋₆ alkyl, (C₁₋₆ alkyl)_(p) amino C₁₋₆alkyl, (aryl)_(p) amino, (aryl)_(p) amino C₁₋₆ alkyl, (aryl C₁₋₆alkyl)_(p) amino, (aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,arylcarbonyloxy, aryl C₁₋₆ alkylcarbonyloxy, (C₁₋₆ alkyl)_(p)aminocarbonyloxy, C₁₋₈ alkylsulfonylamino, arylsulfonylamino, C₁₋₈alkylsulfonylamino C₁₋₆ alkyl, arylsulfonylamino C₁₋₆ alkyl, aryl C₁₋₆alkylsulfonylamino, aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl, C₁₋₈alkoxycarbonylamino, C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,aryloxycarbonylamino C₁₋₈ alkyl, aryl C₁₋₈ alkoxycarbonylamino, arylC₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl, C₁₋₈ alkylcarbonylamino, C₁₋₈alkylcarbonylamino C₁₋₆ alkyl, arylcarbonylamino C₁₋₆ alkyl, aryl C₁₋₆alkylcarbonylamino, aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,aminocarbonylamino C₁₋₆ alkyl, (C₁₋₈ alkyl)_(p) aminocarbonylamino,(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, aminosulfonylaminoC₁₋₆ alkyl, (C₁₋₈ alkyl)_(p) aminosulfonylamino, (C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl, (aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino, (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonylC₁₋₆ alkyl, arylsulfonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonyl, aryl C₁₋₆alkylsulfonyl C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonyl C₁₋₆alkyl, arylcarbonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonyl, aryl C₁₋₆alkylcarbonyl C₁₋₆ alkyl, C₁₋₆ alkylthiocarbonylamino, C₁₋₆alkylthiocarbonylamino C₁₋₆ alkyl, arylthiocarbonylamino C₁₋₆ alkyl,aryl C₁₋₆ alkylthiocarbonylamino, aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆alkyl, (C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl, (aryl)_(p)aminocarbonyl C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and (arylC₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl; or two R³ substituents, whenon the same carbon atom, are taken together with the carbon atom towhich they are attached to form a carbonyl group or a cyclopropyl group,wherein any of the alkyl groups of R³ are either unsubstituted orsubstituted with one to three R¹ substituents, and provided that each R³is selected such that in the resultant compound the carbon atom or atomsto which R³ is attached is itself attached to no more than oneheteroatom; each R⁴ is independently selected from the group consistingof hydrogen,aryl, aminocarbonyl, C₃₋₈ cycloalkyl, amino C₁₋₆ alkyl,(aryl)_(p) aminocarbonyl, (aryl C₁₋₅ alkyl)_(p) aminocarbonyl,hydroxycarbonyl C₁₋₆ alkyl, C₁₋₈ alkyl, aryl C₁₋₆ alkyl, (C₁₋₆alkyl)_(p) amino C₂₋₆ alkyl, (aryl C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,C₁₋₈ alkylsulfonyl, C₁₋₈ alkoxycarbonyl, aryloxycarbonyl, aryl C₁₋₈alkoxycarbonyl, C₁₋₈ alkylcarbonyl, arylcarbonyl, aryl C₁₋₆alkylcarbonyl, (C₁₋₈ alkyl)_(p) aminocarbonyl, aminosulfonyl, C₁₋₈alkylaminosulfonyl, (aryl)_(p) aminosulfonyl, (aryl C₁₋₈ alkyl)_(p)aminosulfonyl, arylsulfonyl, aryl-C₁₋₆ alkylsulfonyl, C₁₋₆alkylthiocarbonyl, arylthiocarbonyl, and aryl C₁₋₆ alkylthiocarbonyl,wherein any of the alkyl groups of R⁴ are either unsubstituted orsubstituted with one to three R¹ substituents; R⁵ and R⁶ are eachindependently selected from the group consisting ofhydrogen, C₁₋₁₀alkyl, aryl, aryl-(CH₂)_(r) --O--(CH₂)_(s) --, aryl-(CH₂)_(r) S(O)_(p)--(CH₂)_(s) --, aryl-(CH₂)_(r) --C(O)--(CH₂)_(s) --, aryl-(CH₂)_(r)--C(O)--N(R⁴)--(CH₂)_(s) --, aryl-(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --,aryl-(CH₂)_(r) N(R⁴)--(CH₂)_(s) --, halogen, hydroxyl, C₁₋₈alkylcarbonylamino, aryl C₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl, (C₁₋₈alkyl)_(p) aminocarbonyl, C₁₋₆ alkylcarbonyloxy, C₃₋₈ cycloalkyl, (C₁₋₆alkyl)_(p) amino, amino C₁₋₆ alkyl, arylaminocarbonyl, aryl C₁₋₅alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C₁₋₆ alkyl,hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl, HC.tbd.C--(CH₂)_(t) --,C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --, C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,aryl-C.tbd.C--(CH₂)_(t) --, C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --, CH₂═CH--(CH₂)_(t) --, C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --, C₃₋₇cycloalkyl-CH═CH--(CH₂)_(t) --, aryl-CH═CH--(CH₂)_(t) --, C₁₋₆alkylaryl-CH═CH--(CH₂)_(t) --, C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --, C₁₋₆alkylaryl-SO₂ --(CH₂)_(t) --, C₁₋₆ alkoxy, aryl C₁₋₆ alkoxy, aryl C₁₋₆alkyl, (C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl, (aryl)_(p) amino, (aryl)_(p)amino C₁₋₆ alkyl, (aryl C₁₋₆ alkyl)_(p) amino, (aryl C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl, arylcarbonyloxy, aryl C₁₋₆ alkylcarbonyloxy, (C₁₋₆alkyl)_(p) aminocarbonyloxy, C₁₋₈ alkylsulfonylamino, arylsulfonylamino,C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl, arylsulfonylamino C₁₋₆ alkyl, arylC₁₋₆ alkylsulfonylamino, aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl, C₁₋₈alkoxycarbonylamino, C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,aryloxycarbonylamino C₁₋₈ alkyl, aryl C₁₋₈ alkoxycarbonylamino, arylC₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl, C₁₋₈ alkylcarbonylamino, C₁₋₈alkylcarbonylamino C₁₋₆ alkyl, arylcarbonylamino C₁₋₆ alkyl, aryl C₁₋₆alkylcarbonylamino, aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,aminocarbonylamino C₁₋₆ alkyl, (C₁₋₈ alkyl)_(p) aminocarbonylamino,(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, aminosulfonylaminoC₁₋₆ alkyl, (C₁₋₈ alkyl)_(p) aminosulfonylamino, (C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl, (aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino , (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonylC₁₋₆ alkyl, arylsulfonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonyl, aryl C₁₋₆alkylsulfonyl C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonyl C₁₋₆alkyl, arylcarbonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonyl, aryl C₁₋₆alkylcarbonyl C₁₋₆ alkyl, C₁₋₆ alkylthiocarbonylamino, C₁₋₆alkylthiocarbonylamino C₁₋₆ alkyl, arylthiocarbonylamino C₁₋₆ alkyl,aryl C₁₋₆ alkylthiocarbonylamino, aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆alkyl, (C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl, (aryl)_(p)aminocarbonyl C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and (arylC₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl; or R⁵ and R⁶ are takentogether with the carbon atom to which they are attached to form acarbonyl group, wherein any of the alkyl groups of R⁵ or R⁶ are eitherunsubstituted or substituted with one to three R¹ substituents, andprovided that each R⁵ and R⁶ are selected such that in the resultantcompound the carbon atom to which R⁵ and R⁶ are attached is itselfattached to no more than one heteroatom; R⁷ and R⁸ are eachindependently selected from the group consisting ofhydrogen, C₁₋₁₀alkyl, aryl, aryl-(CH₂)_(r) --O--(CH₂)_(s) --, aryl-(CH₂)_(r) S(O)_(p)--(CH₂)_(s) --, aryl-(CH₂)_(r) --C(O)--(CH₂)_(s) --, aryl-(CH₂)_(r)--C(O)--N(R⁴)--(CH₂)_(s) --, aryl-(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --,aryl-(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --, halogen, hydroxyl, C₁₋₈alkylcarbonylamino, aryl C₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl, (C₁₋₈alkyl)_(p) aminocarbonyl, C₁₋₆ alkylcarbonyloxy, C₃₋₈ cycloalkyl, (C₁₋₆alkyl)_(p) amino, amino C₁₋₆ alkyl, arylaminocarbonyl, aryl C₁₋₅alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C₁₋₆ alkyl,hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl, HC.tbd.C--(CH₂)_(t) --,C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --, C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,aryl-C.tbd.C--(CH₂)_(t) --, C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --, CH₂═CH--(CH₂)_(t) --, C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --, C₃₋₇cycloalkyl-CH═CH--(CH₂)_(t) --, aryl-CH═CH--(CH₂)_(t) --, C₁₋₆alkylaryl-CH═CH--(CH₂)_(t) --, C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --, C₁₋₆alkylaryl-SO₂ --(CH₂)_(t) --, C₁₋₆ alkoxy, aryl C₁₋₆ alkoxy, aryl C₁₋₆alkyl, (C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl, (aryl)_(p) amino, (aryl)_(p)amino C₁₋₆ alkyl, (aryl C₁₋₆ alkyl)_(p) amino, (aryl C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl, arylcarbonyloxy, aryl C₁₋₆ alkylcarbonyloxy, (C₁₋₆alkyl)_(p) aminocarbonyloxy, C₁₋₈ alkylsulfonylamino, arylcarbonylamino,arylsulfonylamino, C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl, arylsulfonylaminoC₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonylamino, aryl C₁₋₆ alkylsulfonylaminoC₁₋₆ alkyl, C₁₋₈ alkoxycarbonylamino, C₁₋₈ alkoxycarbonylamino C₁₋₈alkyl, aryloxycarbonylamino C₁₋₈ alkyl, aryl C₁₋₈ alkoxycarbonylamino,aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl, C₁₋₈ alkylcarbonylamino C₁₋₆alkyl, arylcarbonylamino C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonylamino, arylC₁₋₆ alkylcarbonylamino C₁₋₆ alkyl, aminocarbonylamino C₁₋₆ alkyl, (C₁₋₈alkyl)_(p) aminocarbonylamino, (C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆alkyl, (aryl)_(p) aminocarbonylamino C₁₋₆ alkyl, arylaminocarbonylamino,(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino, (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl, aminosulfonylamino C₁₋₆ alkyl, (C₁₋₈alkyl)_(p) aminosulfonylamino, (C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆alkyl, (aryl)_(p) aminosulfonylamino C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino, (aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonyl C₁₋₆ alkyl, arylsulfonyl C₁₋₆alkyl, aryl C₁₋₆ alkylsulfonyl, aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkylcarbonyl C₁₋₆ alkyl, arylcarbonyl C₁₋₆ alkyl,aryl C₁₋₆ alkylcarbonyl, aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl, C₁₋₆alkylthiocarbonylamino, C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,arylthiocarbonylamino C₁₋₆ alkyl, aryl C₁₋₆ alkylthiocarbonylamino, arylC₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl, (C₁₋₈ alkyl)_(p) aminocarbonylC₁₋₆ alkyl, (aryl)_(p) aminocarbonyl C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p)aminocarbonyl, (aryl C₁₋₈ alkyl)_(p) --aminocarbonyl C₁₋₆ alkyl, andC₇₋₂₀ polycyclyl C₀₋₈ alkylsulfonylamino; wherein any of the alkylgroups of R⁷ and R⁸ are either unsubstituted or substituted with one tothree R¹ substituents, and provided that each R⁷ and R⁸ are selectedsuch that in the resultant compound the carbon atom to which R⁷ and R⁸are attached is itself attached to no more than one heteroatom; R⁹ isselected from the group consisting ofhydrogen, C₁₋₈ alkyl, aryl, arylC₁₋₈ alkyl, C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl, aryl C₁₋₈ alkylcarbonyloxyC₁₋₄ alkyl, C₁₋₈ alkylaminocarbonylmethylene, and C₁₋₈dialkylaminocarbonylmethylene; R¹⁰, R¹¹, R¹² and R¹³ are eachindependently selected from the group consisting ofhydrogen, C₁₋₈ alkyl,aryl, halogen, hydroxyl, aminocarbonyl, C₃₋₈ cycloalkyl, amino C₁₋₆alkyl, (aryl)_(p) aminocarbonyl, hydroxycarbonyl, (aryl C₁₋₅ alkyl)_(p)aminocarbonyl, hydroxycarbonyl C₁₋₆ alkyl, aryl C₁₋₆ alkyl, (C₁₋₆alkyl)_(p) amino C₁₋₆ alkyl, (aryl C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,C₁₋₈ alkylsulfonyl, C₁₋₈ alkoxycarbonyl, aryloxycarbonyl, aryl C₁₋₈alkoxycarbonyl, C₁₋₈ alkylcarbonyl, arylcarbonyl, aryl C₁₋₆alkylcarbonyl, (C₁₋₈ alkyl)_(p) aminocarbonyl, aminosulfonyl, C₁₋₈alkylaminosulfonyl, (aryl)_(p) aminosulfonyl, (aryl C₁₋₈ alkyl)_(p)aminosulfonyl, C₁₋₆ alkylsulfonyl, arylsulfonyl, aryl C₁₋₆alkylsulfonyl, aryl C₁₋₆ alkylcarbonyl, C₁₋₆ alkylthiocarbonyl,arylthiocarbonyl, aryl C₁₋₆ alkylthiocarbonyl, aryl-(CH₂)_(r)--O--(CH₂)_(s) --, aryl-(CH₂)_(r) S(O)_(p) --(CH₂)_(s) --,aryl-(CH₂)_(r) --C(O)--(CH₂)_(s) --, aryl-(CH₂)_(r)--C(O)--N(R⁴)--(CH₂)_(s) --, aryl-(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --,aryl-(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --, HC.tbd.C--(CH₂)_(t) --, C₁₋₆alkyl-C.tbd.C--(CH₂)_(t) --, C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,aryl-C.tbd.C--(CH₂)_(t) --, C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --, CH₂═CH--(CH₂)_(t) --, C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --, C₃₋₇cycloalkyl-CH═CH--(CH₂)_(t) --, aryl-CH═CH--(CH₂)_(t) --, C₁₋₆alkylaryl-CH═CH--(CH₂)_(t) --, C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --, C₁₋₆alkylaryl-SO₂ --(CH₂)_(t) --, C₁₋₈ alkylcarbonylamino, aryl C₁₋₅ alkoxy,C₁₋₅ alkoxycarbonyl, (C₁₋₈ alkyl)_(p) aminocarbonyl, C₁₋₆alkylcarbonyloxy, (C₁₋₆ alkyl)_(p) amino, aminocarbonyl C₁₋₆ alkyl, C₁₋₆alkoxy, aryl C₁₋₆ alkoxy, (aryl)_(p) amino, (aryl)_(p) amino C₁₋₆ alkyl,(aryl C₁₋₆ alkyl)_(p) amino, (aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,arylcarbonyloxy, aryl C₁₋₆ alkylcarbonyloxy, (C₁₋₆ alkyl)_(p)aminocarbonyloxy, C₁₋₈ alkylsulfonylamino, arylsulfonylamino, C₁₋₈alkylsulfonylamino C₁₋₆ alkyl, arylsulfonylamino C₁₋₆ alkyl, aryl C₁₋₆alkylsulfonylamino, aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl, C₁₋₈alkoxycarbonylamino, C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,aryloxycarbonylamino C₁₋₈ alkyl, aryl C₁₋₈ alkoxycarbonylamino, arylC₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl, C₁₋₈ alkylcarbonylamino, C₁₋₈alkylcarbonylamino C₁₋₆ alkyl, arylcarbonylamino C₁₋₆ alkyl, aryl C₁₋₆alkylcarbonylamino, aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,aminocarbonylamino C₁₋₆ alkyl, (C₁₋₈ alkyl)_(p) aminocarbonylamino,(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, aminosulfonylaminoC₁₋₆ alkyl, (C₁₋₈ alkyl)_(p) aminosulfonylamino, (C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl, (aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino, (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonylC₁₋₆ alkyl, arylsulfonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonyl, aryl C₁₋₆alkylsulfonyl C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonyl C₁₋₆alkyl, arylcarbonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonyl, aryl C₁₋₆alkylcarbonyl C₁₋₆ alkyl, C₁₋₆ alkylthiocarbonylamino, C₁₋₆alkylthiocarbonylamino C₁₋₆ alkyl, arylthiocarbonylamino C₁₋₆ alkyl,aryl C₁₋₆ alkylthiocarbonylamino, aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆alkyl, (C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl, (aryl)_(p)aminocarbonyl C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and (arylC₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl; or R¹⁰ and R¹² are takentogether with the carbon atoms to which they are attached to form a 5-to 7-membered monocyclic aromatic or nonaromatic ring system having 0,1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O,and S wherein the ring nitrogen atoms are unsubstituted or substitutedwith one R¹ substituent and the ring carbon atoms are unsubstituted orsubstituted with one or two R¹ substituents, and wherein any of thealkyl groups of R¹⁰, R¹¹, R¹², and R¹³ are either unsubstituted orsubstituted with one to three R¹ substituents; whereineach m isindependently an integer from 0 to 6; each n is independently an integerfrom 0 to 6 each p is independently an integer from 0 to 2; each r isindependently an integer from 1 to 3; each s is independently an integerfrom 0 to 3; each t is independently an integer from 0 to 3; and each vis independently an integer from 0 to 2;or the pharmaceuticallyacceptable salts thereof.
 2. The compound of claim 1 having a structuralformula selected from the group consisting of ##STR18## wherein thedotted line a represents a single or a double bond, provided that when arepresents a double bond, the double bond carbon atoms are substitutedonly with R¹⁰ and R¹² ;X isa 6-membered monocyclic aromatic ring systemhaving 1 or 2 nitrogen atoms wherein each ring carbon atom isunsubstituted or substituted with one R¹ substituent, or a 9- to14-membered polycyclic ring system, wherein one or more of the rings isaromatic, and wherein the polycyclic ring system has 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O, and S whereinthe ring nitrogen atoms are unsubstituted or substituted with one R¹substituent and the ring carbon atoms are unsubstituted or substitutedwith one or two R¹ substituents.
 3. The compound of claim 2 havingstructural formula ##STR19## wherein the dotted line a represents asingle or a double bond, provided that when a represents a double bond,the double bond carbon atoms are substituted only with R¹⁰ and R¹² ;andX is selected from the group consisting of ##STR20##
 4. The compoundof claim 3 having structural formula
 5. The compound of claim 4 whereinX is
 6. The compound of claim 5 wherein Y is selected from the groupconsisting of --(CH₂)_(m) --,--(CH₂)_(m) --O--(CH₂)_(n) --, --(CH₂)_(m)--NR⁴ --(CH₂)_(n) --, --(CH₂)_(m) --S--(CH₂)_(n) --, --(CH₂)_(m)--SO--(CH₂)_(n) --, --(CH₂)_(m) --SO₂ --(CH₂)_(n) --, --(CH₂)_(m)--O--(CH₂)_(n) --O--(CH₂)_(p) --, --(CH₂)_(m) --O--(CH₂)_(n) --NR⁴--(CH₂)_(p) --, --(CH₂)_(m) --NR⁴ --(CH₂)_(n) --NR⁴ --(CH₂)_(p) --, and--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --O--(CH₂)_(p) --,wherein any methylene(CH₂) carbon atom in Y, other than in R⁴, is unsubstituted orsubstituted by one or two R³ substituents.
 7. The compound of claim 6wherein Y is selected from the group consisting of(CH₂)_(m), (CH₂)_(m)--S--(CH₂)_(n), (CH₂)_(m) --O--(CH₂)_(n), and (CH₂)_(m) --NR⁴--(CH₂)_(n),wherein any methylene (CH₂) carbon atom in Y, other than inR⁴, is unsubstituted or substituted by one or two R³ substituents, m andn are integers from 0-4, and v is
 0. 8. The compound of claim 7 whereinY is(CH₂)_(m) or (CH₂)_(m) --NR⁴ --(CH₂)_(n),wherein any methylene (CH₂)group in Y, other than in R⁴, is unsubstituted or substituted by one ortwo R³ substituents.
 9. The compound of claim 8 wherein each R³ isindependently selected from the group consisting ofhydrogen, fluoro,trifluoromethyl, aryl, C₁₋₈ alkyl, aryl-C₁₋₆ alkyl hydroxyl, oxo,arylaminocarbonyl, aryl C₁₋₅ alkylaminocarbonyl, aminocarbonyl, andaminocarbonyl C₁₋₆ alkyl;and each R⁴ is independently selected from thegroup consisting of hydrogen, aryl, C₃₋₈ cycloalkyl, C₁₋₈ alkyl, C₁₋₈alkylcarbonyl, arylcarbonyl, C₁₋₆ alkylsulfonyl, arylsulfonyl, aryl-C₁₋₆alkylsulfonyl, aryl-C₁₋₆ alkylcarbonyl, C ₁₋₈ alkylaminocarbonyl,aryl-C₁₋₅ alkylaminocarbonyl, aryl-C₁₋₈ alkoxycarbonyl, and C₁₋₈alkoxycarbonyl.
 10. The compound of claim 9 wherein R⁶, R⁷, and R⁸ areeach hydrogen and R⁵ is selected from the group consisting ofhydrogen,aryl, C₁₋₈ alkyl, aryl-C.tbd.C--(CH₂)_(t) --, aryl C₁₋₆ alkyl, CH₂═CH--(CH₂)_(t) --, and HC.tbd.C--(CH₂)_(t) --.
 11. The compound of claim10 wherein R¹⁰, R¹¹, R¹², and R¹³ are each independently selected fromthe group consisting of hydrogen, aryl, C₁₋₆ alkyl, and arylC₁₋₆ alkyl.12. The compound of claim 10 wherein R⁹ is selected from the groupconsisting of hydrogen, methyl, and ethyl.
 13. The compound of claim 12wherein R⁹ is hydrogen.
 14. The compound of claim 9 wherein R⁵, R⁶, andR⁸ are each hydrogen and R⁷ is selected from the group consistingofhydrogen, aryl, C₁₋₈ alkylcarbonylamino, C₁₋₈ alkylsulfonylamino,arylcarbonylamino, arylsulfonylamino, C₁₋₈ alkylsulfonylamino C₁₋₆alkyl, arylsulfonylamino C₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonylamino, arylC₁₋₆ alkylsulfonylamino C₁₋₆ alkyl, C₁₋₈ alkoxycarbonylamino, C₁₋₈alkoxycarbonylamino C₁₋₈ alkyl, aryloxycarbonylamino C₁₋₈ alkyl, arylC₁₋₈ alkoxycarbonylamino, aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl, C₁₋₈alkylcarbonylamino C₁₋₆ alkyl, arylcarbonylamino C₁₋₆ alkyl, aryl C₁₋₆alkylcarbonylamino, aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,aminocarbonylamino C₁₋₆ alkyl, (C₁₋₈ alkyl)_(p) aminocarbonylamino,(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl, arylaminocarbonylamino, (aryl C₁₋₈alkyl)_(p) aminocarbonylamino, (aryl C₁₋₈ alkyl)_(p) aminocarbonylaminoC₁₋₆ alkyl, aminosulfonylamino C₁₋₆ alkyl, (C₁₋₈ alkyl)_(p)aminosulfonylamino, (C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino, (aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,C₁₋₆ alkylthiocarbonylamino, C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,arylthiocarbonylamino C₁₋₆ alkyl, aryl C₁₋₆ alkylthiocarbonylamino, andaryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl.
 15. The compound of claim14 wherein R⁷ is selected from the group consisting ofhydrogen, aryl,C₁₋₈ alkylcarbonylamino, aryl C₁₋₆ alkylcarbonylamino,arylcarbonylamino, C₁₋₈ alkylsulfonylamino, aryl C₁₋₆alkylsulfonylamino, arylsulfonylamino, C₁₋₈ alkoxycarbonylamino, arylC₁₋₈ alkoxycarbonylamino, arylaminocarbonylamino, (C₁₋₈ alkyl)_(p)aminocarbonylamino, (aryl C₁₋₈ alkyl)_(p) aminocarbonylamino, (C₁₋₈alkyl)_(p) aminosulfonylamino, and (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino.
 16. The compound of claim 15 wherein R¹⁰, R¹¹, R¹²,and R¹³ are each independently selected from the group consisting ofhydrogen, aryl, C₁₋₆ alkyl, and arylC₁₋₆ alkyl.
 17. The compound ofclaim 15 wherein R⁹ is selected from the group consisting of hydrogen,methyl, and ethyl.
 18. The compound of claim 17 wherein R⁹ is hydrogen.19. The compound of claim 9 selected from the group consistingof3(R)-(3-fluoro-phenyl)-3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3(R)-yl}-propionicacid,3(R)-(3-fluoro-phenyl)-3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3(S)-yl}-propionicacid,3(S)-(3-fluoro-phenyl)-3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3(R)-yl}-propionicacid,3(S)-(3-fluoro-phenyl)-3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3(S)-yl}-propionicacid,3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl}-3(R)-quinolin-3(R)-yl-propionicacid,3-{2-oxo-1-(3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl}-3(R)-quinolin-3(S)-yl-propionicacid,3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl}-3(S)-quinolin-3(R)-yl-propionicacid,3-{2-oxo-1-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-3-yl}-3(S)-quinolin-3(S)-yl-propionicacid,or the pharmaceutically acceptable salts thereof.
 20. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier.
 21. The composition of claim20 which further comprises an active ingredient selected from the groupconsisting ofa) an organic bisphosphonate or a pharmaceuticallyacceptable salt thereof, b) an estrogen receptor modulator, c) acytotoxic/antiproliferative agent, d) a matrix metalloproteinaseinhibitor, e) an inhibitor of VEGF, f) an inhibitor of Flk-1/KDR, Flt-1,Tck/Tie-2, or Tie-1, g) a cathepsin K inhibitor, h) an inhibitor ofosteoclast proton ATPase, and i) a farnesyl transferase inhibitor or ageranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyltransferase inhibitor;and mixtures thereof.
 22. The composition of claim21 wherein said active ingredient is selected from the group consistingofa) an organic bisphosphonate or a pharmaceutically acceptable saltthereof, b) an estrogen receptor modulator, c) a cathepsin K inhibitor,and d) an inhibitor of osteoclast proton ATPase;and mixtures thereof.23. The composition of claim 22 wherein said organic bisphosphonate orpharmaceutically acceptable salt thereof is alendronate monosodiumtrihydrate.
 24. A method of eliciting an ανβ3 integrin receptorantagonizing effect in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of acompound according to claim
 1. 25. The method of claim 24 wherein theανβ3 antagonizing effect is selected from the group consisting ofinhibition of bone resorption, restenosis, angiogenesis, diabeticretinopathy, macular degeneration, inflammation, viral disease, andtumor growth.
 26. The method of claim 25 wherein the ανβ3 antagonizingeffect is the inhibition of bone resorption.
 27. A method of elicitingan ανβ5 integrin receptor is an antagonizing effect in a mammal in needthereof, comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim
 1. 28. The method ofclaim 27 wherein the ανβ5 antagonizing effect is selected from the groupconsisting of inhibition of restenosis, angiogenesis, diabeticretinopathy, macular degeneration, inflammation, and tumor growth.
 29. Amethod of eliciting a dual ανβ3/ανβ5 integrin antagonizing effect in amammal in need thereof, comprising administering to the mammal atherapeutically effective amount of a compound according to claim
 1. 30.The method of claim 24 wherein the dual ανβ3/ανβ5 antagonizing effect isselected from the group consisting of inhibition of bone resorption,restenosis, angiogenesis, diabetic retinopathy, macular degeneration,inflammation, viral disease, and tumor growth.
 31. A method of elicitingan ανβ3, ανβ5, or dual ανβ3/ανβ5 integrin receptor antagonizing effectin a mammal in need thereof, comprising administering to the mammal atherapeutically effective amount of the composition of claim
 20. 32. Amethod of treating or preventing a condition mediated by antagonism ofan ανβ3, ανβ5, or dual ανβ3/ανβ5 integrin receptor antagonizing effectin a mammal in need thereof, comprising administering to the mammal atherapeutically effective amount of the composition of claim
 20. 33. Amethod of inhibiting bone resorption in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of the composition of claim
 20. 34. A method of inhibiting boneresorption in a mammal in need thereof, comprising administering to themammal a therapeutically effective amount of the composition of claim22.
 35. A method of treating or preventing osteoporosis in a mammal inneed thereof, comprising administering to the mammal a therapeuticallyeffective amount of the composition of claim
 20. 36. A method oftreating tumor growth in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of thecomposition of claim 20.